Bisamide sarcomere activating compounds and uses thereof

ABSTRACT

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising a compound of the invention, a method for manufacturing compounds of the invention and therapeutic uses thereof.

FIELD OF THE INVENTION

The invention relates to substituted bis amide derivatives, particularlyto chemical entities that selectively modulate the cardiac sarcomere.More particularly, the invention relates to substituted bis-amidederivatives that are troponin activators, and specifically to saidcompounds, pharmaceutical compositions and methods of treatment forheart disease.

BACKGROUND OF THE INVENTION

The “sarcomere” is an elegantly organized cellular structure found incardiac and skeletal muscle made up of interdigitating thin and thickfilaments; it comprises nearly 60% of cardiac cell volume. The thickfilaments are composed of “myosin,” the protein responsible fortransducing chemical energy (ATP hydrolysis) into force and directedmovement. Myosin and its functionally related cousins are called motorproteins. The thin filaments are composed of a complex of proteins. Oneof these proteins, “actin” (a filamentous polymer) is the substrate uponwhich myosin pulls during force generation. Bound to actin are a set ofregulatory proteins, the “troponin complex” and “tropomyosin,” whichmake the actin-myosin interaction dependent on changes in intracellularCa²⁺ levels. With each heartbeat, Ca²⁺ levels rise and fall, initiatingcardiac muscle contraction and then cardiac muscle relaxation Each ofthe components of the sarcomere contributes to its contractile response.

Myosin is the most extensively studied of all the motor proteins. Of thethirteen distinct classes of myosin in human cells, the myosin-II classis responsible for contraction of skeletal, cardiac, and smooth muscle.This class of myosin is significantly different in amino acidcomposition and in overall structure from myosin in the other twelvedistinct classes. Myosin-II consists of two globular head domains linkedtogether by a long alpha-helical coiled-coiled tail that assembles withother myosin-IIs to form the core of the sarcomeres thick filament. Theglobular heads have a catalytic domain where the actin binding and ATPfunctions of myosin take place. Once bound to an actin filament, therelease of phosphate (cf. ATP to ADP) leads to a change in structuralconformation of the catalytic domain that in turn alters the orientationof the light-chain binding lever arm domain that extends from theglobular head; this movement is termed the powerstroke. This change inorientation of the myosin head in relationship to actin causes the thickfilament of which it is a part to move with respect to the thin actinfilament to which it is bound. Un-binding of the globular head from theactin filament (also Ca²⁺ modulated) coupled with return of thecatalytic domain and light chain to their startingconformation/orientation completes the contraction and relaxation cycle.

Mammalian heart muscle consists of two forms of cardiac myosin, alphaand beta, and they are well characterized. The beta form is thepredominant form (>90 percent) in adult human cardiac muscle. Both havebeen observed to be regulated in human heart failure conditions at bothtranscriptional and translational levels, with the alpha form beingdown-regulated in heart failure.

The sequences of all of the human skeletal, cardiac, and smooth musclemyosins have been determined. While the cardiac alpha and beta myosinsare very similar (93% identity), they are both considerably differentfrom human smooth muscle (42% identity) and more closely related toskeletal myosins (80% identity). Conveniently, cardiac muscle myosinsare incredibly conserved across mammalian species. For example, bothalpha and beta cardiac myosins are >96% conserved between humans andrats, and the available 250-residue sequence of porcine cardiac betamyosin is 100% conserved with the corresponding human cardiac betamyosin sequence. Such sequence conservation contributes to thepredictability of studying myosin based therapeutics in animal basedmodels of heart failure.

The components of the cardiac sarcomere present targets for thetreatment of heart failure, for example by increasing contractility orfacilitating complete relaxation to modulate systolic and diastolicfunction, respectively.

Congestive heart failure (“CHF”) is not a specific disease, but rather aconstellation of signs and symptoms, all of which are caused by aninability of the heart to adequately respond to exertion by increasingcardiac output. The dominant pathophysiology associated with CHF issystolic dysfunction, an impairment of cardiac contractility (with aconsequent reduction in the amount of blood ejected with eachheartbeat). Systolic dysfunction with compensatory dilation of theventricular cavities results in the most common form of heart failure,“dilated cardiomyopathy,” which is often considered to be one in thesame as CHF. The counterpoint to systolic dysfunction is diastolicdysfunction, an impairment of the ability to fill the ventricles withblood, which can also result in heart failure even with preserved leftventricular function. Congestive heart failure is ultimately associatedwith improper function of the cardiac myocyte itself, involving adecrease in its ability to contract and relax.

Many of the same underlying conditions can give rise to systolic and/ordiastolic dysfunction, such as atherosclerosis, hypertension, viralinfection, valvular dysfunction, and genetic disorders. Patients withthese conditions typically present with the same classical symptoms:shortness of breath, edema and overwhelming fatigue. In approximatelyhalf of the patients with dilated cardiomyopathy, the cause of theirheart dysfunction is ischemic heart disease due to coronaryatherosclerosis. These patients have had either a single myocardialinfarction or multiple myocardial infarctions; here, the consequentscarring and remodeling results in the development of a dilated andhypocontractile heart. At times the causative agent cannot beidentified, so the disease is referred to as “idiopathic dilatedcardiomyopathy.” Irrespective of ischemic or other origin, patients withdilated cardiomyopathy share an abysmal prognosis, excessive morbidityand high mortality.

The prevalence of CHF has grown to epidemic proportions as thepopulation ages and as cardiologists have become more successful atreducing mortality from ischemic heart disease, the most common preludeto CHF. Roughly 4.6 million people in the United States have beendiagnosed with CHF; the incidence of such diagnosis is approaching 10per 1000 after 65 years of age. Hospitalization for CHF is usually theresult of inadequate outpatient therapy. Hospital discharges for CHFrose from 377,000 (in 1979) to 970,000 (in 2002) making CHF the mostcommon discharge diagnosis in people age 65 and over. The five-yearmortality from CHF approaches 50%. Hence, while therapies for heartdisease have greatly improved and life expectancies have extended overthe last several years, new and better therapies continue to be sought,particularly for CHF.

“Acute” congestive heart failure (also known as acute “decompensated”heart failure) involves a precipitous drop in cardiac function resultingfrom a variety of causes. For example in a patient who already hascongestive heart failure, a new myocardial infarction, discontinuationof medications, and dietary indiscretions may all lead to accumulationof edema fluid and metabolic insufficiency even in the resting state. Atherapeutic agent that increases cardiac function during such an acuteepisode could assist in relieving this metabolic insufficiency andspeeding the removal of edema, facilitating the return to the morestable “compensated” congestive heart failure state. Patients with veryadvanced congestive heart failure particularly those at the end stage ofthe disease also could benefit from a therapeutic agent that increasescardiac function, for example, for stabilization while waiting for aheart transplant. Other potential benefits could be provided to patientscoming off a bypass pump, for example, by administration of an agentthat assists the stopped or slowed heart in resuming normal function.Patients who have diastolic dysfunction (insufficient relaxation of theheart muscle) could benefit from a therapeutic agent that modulatesrelaxation.

Inotropes are drugs that increase the contractile ability of the heart.As a group, all current inotropes have failed to meet the gold standardfor heart failure therapy, i.e., to prolong patient survival. Inaddition, current agents are poorly selective for cardiac tissue, inpart leading to recognized adverse effects that limit their use. Despitethis fact, intravenous inotropes continue to be widely used in acuteheart failure (e.g., to allow for reinstitution of oral medications orto bridge patients to heart transplantation) whereas in chronic heartfailure, orally given digoxin is used as an inotrope to relieve patientsymptoms, improve the quality of life, and reduce hospital admissions.

Current inotropic therapies improve contractility by increasing thecalcium transient via the adenylyl cyclase pathway, or by delaying cAMPdegradation through inhibition of phosphodiesterase (PDE), which can bedetrimental to patients with heart failure.

New approaches are needed to improve cardiac function in congestiveheart failure. There remains a need for agents that exploit differentmechanisms of action and may have better outcomes in terms of relief ofsymptoms, safety, and patient mortality, both short-term and long-term.

SUMMARY OF THE INVENTION

The present invention provides new compounds which activate the cardiacsarcomere. In particular, compounds of the invention may bind to theTroponin C/Troponin I interface to increase activity of the cardiacsarcomere.

The invention provides, in one aspect, bis-amide compounds whichmodulate the activity of cardiac sarcomere. Preferably, the bis-amidecompounds of the invention are troponin activators interface to increaseactivity of the cardiac sarcomere. In some embodiments, the bis-amidecompounds of the invention are troponin activators that activate thecardiac sarcomere. In some embodiments, the bis-amide compounds of theinvention are troponin activators that increase the activity of thecardiac sarcomere. In certain preferred applications, the bis-amidecompounds of the invention are compounds that activate the cardiacsarcomere by binding to the Troponin C and Troponin I interface.

The bis-amide compounds of the invention are compounds and saltsaccording Formula (I):

Also provided is a pharmaceutical composition comprising apharmaceutically acceptable excipient, carrier or adjuvant and at leastone compound of formula (I) or subformulae thereof.

Also provided is a packaged pharmaceutical composition, comprising apharmaceutical composition comprising a pharmaceutically acceptableexcipient, carrier or adjuvant and at least one compound of formula (I)or subformulae thereof, and instructions for using the composition totreat a patient suffering from a heart disease.

Also provided is a method of treating heart disease in a mammal whichmethod comprises administering to a mammal in need thereof atherapeutically effective amount of at least one compound of formula (I)or subformulae thereof or a pharmaceutical composition comprising apharmaceutically acceptable excipient, carrier or adjuvant and at leastone compound of formula (I) or subformulae thereof.

Also provided is a method for modulating the cardiac sarcomere in amammal which method comprises administering to a mammal in need thereofa therapeutically effective amount of at least one compound of formula(I) or subformulae thereof or a pharmaceutical composition comprising apharmaceutically acceptable excipient, carrier or adjuvant and at leastone compound of formula (I) or subformulae thereof.

Also provided is a method for potentiating Troponin C, Troponin I or theinterface of Troponin C and Troponin I to increase activity of thecardiac sarcomere in a mammal which method comprises administering to amammal in need thereof a therapeutically effective amount of at leastone compound of formula (I) or subformulae thereof or a pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient, carrieror adjuvant and at least one compound of formula (I) or subformulaethereof.

Also provided is the use, in the manufacture of a medicament fortreating heart disease, of at least one compound of formula I orsubformulae thereof.

Other aspects and embodiments will be apparent to those skilled in theart form the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The invention related generally to compounds of Formula I and salts andtautomers thereof which activate the cardiac sarcomere. Compounds andsalts thereof according to Formula I are generally represented by thestructure:

wherein

or a 5-member heteroaryl having 1 or 2 ring heteroatoms independentlyselected from N, O, and S which is optionally substituted with 1 or 2groups selected from C₁-C₆alkyl and halo C₁-C₆alkyl;A is absent, oxygen, N(H), N(C₁-C₆alkyl) or CR¹¹R^(11a);X¹ is N or CR²;X², X³, X⁴ and X⁵ are each independently selected from N and CR³provided that 0, 1, or 2 of X¹, X², X³, X⁴ and X⁵ are N and theremainder are CR² or CR³;R¹ is selected from the group consisting of hydrogen, C₁-C₆alkyl, haloC₁-C₆alkyl, hydroxy C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₇cycloalkyl optionally substituted with 1 or 2 groups selected fromhydroxy, halogen, and C₁-C₄alkyl, hydroxy C₃-C₇cycloalkyl,C₃-C₇cycloalkylC₁-C₄alkyl, hydroxy C₃-C₇cycloalkylC₁-C₄alkyl, and 4 to 7member heterocycloalkyl having 1 or 2 ring heteroatoms independentlyselected from N, O and S, which heterocycloalkyl is optionallysubstituted with 1 or 2 groups selected from oxo, hydroxy, halogen andC₁-C₄alkyl;R^(1a) is selected from the group consisting of hydrogen, C₁-C₆alkyl andhalogen;R² is selected from the group consisting of hydrogen, halogen,C₁-C₆alkyl, haloC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl,C₃-C₇cycloalkylC₁-C₄alkyl, C₁-C₆alkoxy, haloC₁-C₆alkoxy and SF₅; orR¹ and R², taken in combination form a divalent group selected from—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, —CH₂OCH₂—, —OCH₂CH₂, —CH₂N(H)CH₂—and —CH₂N(C₁-C₄alkyl)CH₂—, each of which is optionally substituted withC₁-C₄alkyl or hydroxyC₁-C₄alkyl and wherein the oxygen of —OCH₂CH₂— or—OCH₂— is attached to the CR² carbon;R³ is independently selected from the group consisting of hydrogen,halogen, C₁-C₆alkyl, haloC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₇cycloalkyl, C₃-C₇cycloalkylC₁-C₄alkyl, C₁-C₆alkoxy, haloC₁-C₆alkoxyand SF₅Z¹ is N or CR⁵;Z² is N or CR⁶;Z³ is N or CR⁷, wherein 0, 1, or 2 of Z¹, Z² and Z³ can be N;R⁴ is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, haloC₁-C₆alkyl,C₃-C₇cycloalkyl, cyano, benzoyl, SO₂—R⁸ or 4 to 7 memberheterocycloalkyl having a ring heteroatom selected from N, O and S whichheterocycloalkyl is substituted with 0, 1 or 2 groups independentlyselected from the group consisting of halogen, oxo, C₁-C₆alkyl,C(O)C₁-C₆alkyl, and SO₂R⁸, and wherein when R⁴ is C₁-C₆alkyl,haloC₁-C₆alkyl, or C₃-C₇cycloalkyl, it is optionally substituted withone or two groups independently selected from hydroxy, cyano, CO₂H,CO₂C₁-C₆alkyl and C(O)NH₂;R⁵ is hydrogen, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkoxy, amino, mono- ordi-C₁-C₆alkylamino, C₃-C₇cycloalkylamino or —N(H)C(O)C₁-C₄alkyl, whereeach alkyl or cycloalkyl is optionally substituted with hydroxy;R⁶ is hydrogen, C₁-C₆alkyl, haloC₁-C₆alkyl or halogen;R⁵ and R⁶, taken in combination with the interposed atoms, form a 5- or6-membered heteroaryl having 1 or 2 ring heteroatoms selected from N, O,and S;R⁷ and R⁸ taken in combination form a divalent group selected from—CH₂CH₂— and —CH₂CH₂CH₂—; orR⁷ is hydrogen, C₁-C₆alkyl, or SO₂C₁-C₆alkyl; R⁸ is C₁-C₆alkyl,NR^(8d)R^(8e), C₃-C₇cycloalkyl, haloC₁-C₆alkyl or benzyl, wherein eachalkyl, cycloalkyl or haloalkyl is optionally substituted with hydroxy,CO₂H, CO₂C₁-C₆alkyl or C(O)NH₂; or R⁸ is a group of the formula:

whereinp is 1 or 2;R^(8a) is hydrogen, C₁-C₆alkyl, benzyl, or phenyl optionally substitutedwith C₁-C₆alkyl or halogen;R^(8b) is hydrogen, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,haloC₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkoxyC₁-C₄alkyl, C₃-C₇cycloalkyl,cyano, amino, N(H)C(O)C₁-C₆alkyl, N(H)C(O)C₃-C₇cycloalkyl,N(H)C(O)haloC₁-C₆alkyl, CO₂H, C(O)NH₂, C(O)NH(C₁-C₆alkyl),C(O)N(C₁-C₆alkyl)₂, C(O)C₁-C₆alkyl, C(O)haloC₁-C₆alkyl, SO₂C₁-C₆alkyl,phenyl optionally substituted with halogen, C₁-C₄alkyl orhaloC₁-C₄alkyl, benzyl optionally substituted with halogen, phenoxyoptionally substituted with halogen, 4 to 7 member heterocycloalkylhaving 1 or 2 ring heteroatoms selected from N, O and S, or 5 or 6member heteroaryl having 1 ring heteroatom selected from N, O or S and0, 1 or 2 additional ring nitrogen atoms, which heteroaryl is optionallysubstituted with 1 or 2 C₁-C₆alkyl, and wherein the alkoxy is optionallysubstituted with halogen, phenyl or halogen substituted phenyl;R^(8c) is hydrogen, halogen, hydroxy or C₁-C₆alkyl; orCR^(8b)R^(8c), taken in combination, forms a spirocyclic 3 to 6 membercarboxycle or a 4 to 6 member heterocycle having a ring heteroatomselected from N, O and S, which spirocycle is optionally substitutedwith hydroxy, C₁-C₄alkyl, haloC₁-C₄alkyl or C₁-C₄alkoxy;R^(8d) is hydrogen, C₁-C₆alkyl, haloC₁-C₆alkyl, C₃-C₇cycloalkyl, or 4 to7 member heterocycloalkyl having 1 ring heteroatom selected from N, Oand S and 0 or 1 additional ring nitrogen atoms, which heterocycloalkylis optionally substituted with 1 or 2 substituents independentlyselected from hydroxy, halogen, oxo, C₁-C₆alkyl, and C₁-C₆alkoxy;R^(8e) is hydrogen or C₁-C₆alkyl; orNR^(8d)R^(8e), taken in combination, forms a 4 to 7 memberheterocycloalkyl optionally comprising an additional ring heteroatomselected from N, O and S, which heterocycloalkyl is optionallysubstituted with 1 or 2 substituents independently selected fromhydroxy, halogen, oxo, C₁-C₆alkyl, C₁-C₆alkoxy and heteroaryl, whichheteroaryl has 5 or 6 ring atoms and has one ring heteroatom selectedfrom N, O and S and 0 or 1 additional ring nitrogen atom, orNR^(8d)R^(8e), taken in combination, forms a 5 or 6 member heteroaryl,optionally comprising 1 additional ring heteroatom selected from N, Oand S;R⁹ is hydrogen or C₁-C₆alkyl;R¹⁰ and R^(10a) are each independently selected from the groupconsisting of hydrogen, halogen and C₁-C₆alkyl; orR⁹ and R¹⁰, taken in combination, form a divalent bridge selected fromO, CH₂, and CH₂CH₂ and R^(10a) is hydrogen;R^(11a) is hydrogen or halogen;R¹² is hydrogen or halogen;R¹¹ is selected from the group consisting of hydrogen, halogen,C₁-C₆alkyl, N(H)C₁-C₆alkyl and N(H)C₃-C₇cycloalkyl; orR¹¹ and R¹², taken in combination, form a double bond;R^(13a) is hydrogen or C₁-C₆alkyl;R¹³ is C₁-C₆alkyl, C₃-C₇cycloalkyl or C₃-C₇cycloalkylC₁-C₆alkyl;R¹⁴ is C₁-C₅alkyl, C₃-C₇cycloalkyl or C₃-C₇cycloalkylC₁-C₆alkyl; orR¹³ and R¹⁴, taken in combination with the interposed C and N atoms,form a saturated or partially unsaturated 4 to 7 member heterocyclewhich heterocycle further comprises 0 or 1 additional ring heteroatomsselected from N, O and S, which heterocycle is optionally fused to abenzo ring or a saturated carbocycle having 3 to 7 ring atoms, or whichheterocycle is optionally taken together with a saturated carbocyclehaving 3 to 7 ring atoms to form a spirocyclic ring, and wherein theheterocycle is optionally substituted with 0, 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxy,oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, haloC₁-C₆alkyl,C₁-C₆alkoxy, C₃-C₇cycloalkyl, O—C(O)pyridine substituted with C₁-C₄alkyland haloC₁-C₄alkyl; andR¹⁵ is hydrogen or halogen;with the proviso that

(1) when R⁴ is SO₂CH₃, then at least one occurrence of R¹, R² or R³ isnot hydrogen;

(2) when R⁴ is halogen, trifluoromethyl or cyano and R⁶ is hydrogen orhalogen, then at least one occurrence of R¹ or R² is not hydrogen or R¹is not methyl;

(3) when R⁵ is C₁-C₆alkoxy, then R⁴ is not hydrogen or halogen; and

(4) when R⁴ is C₁-C₅alkoxy or C₁-C₆alkyl, then R² is not hydrogen.

In certain aspects of the first embodiment, compound of Formula Iinclude compounds wherein Q is

and all other variables are as defined in the first embodiment. Incertain aspects, Q is

and all other variables are as defined in the first embodiment. Incertain aspects, Q is

and all other variables are as defined in the first embodiment.

In certain aspects of the first embodiment, compounds of Formula Iinclude compounds of Formula Ia:

where variables Q, X¹, X², X³, X⁴, X⁵, R¹, R¹³, R^(13a) and R¹⁴ are asdefined in the first embodiment.

In other aspects of the first embodiment, compounds of Formula I includecompounds of Formula Ib:

where variables Q, X¹, X², X³, X⁴, X⁵, R¹, R¹³, R^(13a) and R¹⁴ are asdefined in the first embodiment.

In a second embodiment, the invention provides compounds of the firstembodiment in which X¹ is CR², X² is N or CR³, X³ is CR^(3a), X⁴ is N orCR³ and X⁵ is CR³;

R² is hydrogen, halogen, C₁-C₄alkyl, cyclopropyl, haloC₁-C₄alkyl,C₁-C₄alkoxy or haloC₁-C₄alkoxy;

R³ is independently selected at each occurrence from the groupconsisting of hydrogen, halogen, C₁-C₄alkyl, cyclopropyl,haloC₁-C₄alkyl, C₁-C₄alkoxy and haloC₁-C₄alkoxy; and

R^(3a) is halogen, C₁-C₆alkyl, haloC₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₇cycloalkyl, C₃-C₇cycloalkylC₁-C₄alkyl, C₁-C₆alkoxy,haloC₁-C₆alkoxy or SF₅.

In a third embodiment, the invention provides compounds of the first orsecond embodiment in which X¹ is CR²; R² is hydrogen, halogen,C₁-C₄alkyl or C₁-C₄alkoxy; X² is CH or N; X³ is CR^(3a); R^(3a) ishalogen, C₁-C₄alkyl, haloC₁-C₄alkyl, haloC₁-C₆alkoxy or SF₅; X⁴ is CR³or N; R³ is hydrogen or halogen; and X⁵ is CH.

In a fourth embodiment, the invention provides compounds of any one ofthe first to third embodiment in which R² is hydrogen, halogen, methyl,ethyl, methoxy or ethoxy; X² and X⁵ are each CH; X³ is CR^(3a); R^(3a)is halogen, methyl, ethyl, fluoromethyl, difluoromethyl,trifluoromethyl, trifluormethoxy or SF₅; X⁴ is CR³; and R³ is hydrogenor halogen. In some aspects, R^(3a) is fluoro, chloro, CH₂F, CHF₂, orCF₃. In certain aspects, X¹ is CR²; R² is halogen; X² and X⁵ are eachCH; X³ is CR^(3a); R^(3a) is halogen or trifluoromethyl; X⁴ is CR³; andR³ is halogen.

In a fifth embodiment, the invention provides compounds of any one ofthe first to fourth embodiment in which R¹ is selected from the groupconsisting of hydrogen, C₁-C₆alkyl, halo C₁-C₆alkyl, C₃-C₇cycloalkyl,C₃-C₇cycloalkylmethyl, and 4 to 6 member heterocycloalkyl having a ringheteroatom selected from N and O, which heterocycloalkyl is optionallysubstituted with 1 or 2 groups selected from oxo, halogen, and hydroxy,and wherein the alkyl or cycloalkyl is optionally substituted withhydroxy. In an embodiment, the invention provides compounds of any oneof the first to fourth embodiments in which R¹ is selected from thegroup consisting of C₂-C₆alkyl, halo C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₇cycloalkyl, C₃-C₇cycloalkylC₁-C₄alkyl, and 4 to 7member heterocycloalkyl having 1 or 2 ring heteroatoms independentlyselected from N, O and S, which heterocycloalkyl is optionallysubstituted with 1 or 2 groups selected from oxo, hydroxy, halogen andC₁-C₄alkyl and wherein the alkyl or cycloalkyl is optionally substitutedwith hydroxy;

In a sixth embodiment, the invention provides compounds of any one ofthe first to fifth embodiment in which R¹ is C₁-C₄alkyl,trifluoromethyl, C₃-C₅cycloalkyl, C₃-C₅cycloalkylmethyl, oxetanyl,tetrahydrofuryl, or azetidinyl, wherein each alkyl, cycloalkyl, oxetanylor azetidinyl is optionally substituted with hydroxy or halogen.

In a seventh embodiment, the invention provides compounds of any one ofthe first to sixth embodiment in which R¹ is methyl, isopropyl,cyclopropyl, cyclopropylmethyl, cyclobutyl, oxetanyl or1-hydroxycyclopropyl. In certain aspects of the seventh embodiment, R¹is methyl, isopropyl, cyclopropyl or oxetanyl. In certain preferredaspects of the seventh embodiment, R¹ is cyclopropyl. In certainaspects, R¹ is methyl, isopropyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, oxetanyl, difluoromethyl, 1-hydroxycyclopropyl,3-hydroxycyclobutyl, 3-hydroxy-3-methylcyclobutyl, 3-fluorooxetanyl oroxopyrrolidinyl.

In an eighth embodiment, the invention provides compounds of any one ofthe first to seventh embodiment in which R¹³ and R¹⁴ are eachindependently selected from the group consisting of C₁-C₄alkyl,C₃-C₅cycloalkyl and C₃-C₅cycloalkylmethyl; and R^(13a) is hydrogen.

In a ninth embodiment, the invention provides compounds of any one ofthe first to eighth embodiment in which R¹³ and R¹⁴ are each methyl andR^(13a) is hydrogen.

In a tenth embodiment, the invention provides compounds of any one ofthe first to seventh embodiment in which R^(13a) is hydrogen; and R¹³and R¹⁴, taken in combination with the interposed C and N atoms, form asaturated or partially unsaturated 4 to 6 member heterocycle, whichheterocycle further comprises 0 or 1 additional ring heteroatomsselected from N, O and S, wherein the heterocycle is optionally fused toa saturated carbocycle having 3 to 7 ring atoms, or which heterocycle isoptionally taken together with a saturated carbocyle having 3 to 7 ringatoms to form a spirocyclic ring, and wherein the heterocycle isoptionally substituted with 0, 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxy, C₁-C₆alkyl,haloC₁-C₆alkyl, C₁-C₆alkoxy and C₃-C₇cycloalkyl.

In an eleventh embodiment, the invention provides compounds of any oneof the first to seventh and tenth embodiment in which R^(13a) ishydrogen; and R¹³ and R¹⁴, taken in combination with the interposed Cand N atoms, form a heterocyclic ring selected from the group consistingof azetidine, pyrrolidine, thiazolidine, piperidine and morpholine,wherein the heterocyclic ring is optionally fused to a cyclopropyl ringand the heterocyclic ring is further optionally substituted with 1 or 2substituents independently selected from the group consisting ofhalogen, hydroxy, methyl, hydroxymethyl, methoxy and cyclopropyl.

In a twelfth embodiment, the invention provides compounds of any one ofthe first to seventh, tenth and eleventh embodiment in which R^(13a) ishydrogen; and R¹³ and R¹⁴, taken in combination with the interposed Cand N atoms, form a pyrrolidine ring, wherein the pyrrolidine ring isoptionally fused with to a cyclopropyl ring and the pyrrolidine ring isfurther optionally substituted with 1 or 2 substituents independentlyselected from the group consisting of halogen, hydroxy, methyl,hydroxymethyl and cyclopropyl. In certain aspects of the twelfthembodiment, R^(13a) is hydrogen; and R¹³ and R¹⁴, taken in combinationwith the interposed C and N atoms, form a pyrrolidine ring, wherein thepyrrolidine ring is fused to a cyclopropyl ring and the pyrrolidine ringis unsubstituted. In certain aspects of the twelfth embodiment, R^(13a)is hydrogen; R¹³ and R¹⁴, taken in combination with the interposed C andN atoms, form a pyrrolidine ring, wherein the pyrrolidine ring is fusedto a cyclopropyl ring and the pyrrolidine ring is unsubstituted; X¹ isCR²; R² is halogen; X² and X⁵ are each CH; X³ is CR^(3a); R^(3a) ishalogen or trifluoromethyl; X⁴ is CR³; and R³ is halogen. In certainaspects of the twelfth embodiment, R^(13a) is hydrogen; R¹³ and R¹⁴,taken in combination with the interposed C and N atoms, form apyrrolidine ring, wherein the pyrrolidine ring is fused to a cyclopropylring and the pyrrolidine ring is unsubstituted, and R¹ is cyclopropyl.

In a thirteenth embodiment, the invention provides compounds of any oneof the first to twelfth embodiment in which Q in which Q is

wherein Z² is N or CR⁶; Z³ is N or CR⁷, wherein 0 or 1 of Z² and Z³ canbe N; R⁴ is C₁-C₄alkyl, C₁-C₄alkoxy, cyano, SO₂—R⁸, or 4 to 7 memberheterocycloalkyl having a ring heteroatom selected from N, O and S whichheterocycloalkyl is substituted with 0, 1 or 2 groups independentlyselected from the group consisting of halogen, oxo, C₁-C₆alkyl,C(O)C₁-C₆alkyl, and SO₂R⁸ and wherein each alkyl or cycloalkyl isoptionally substituted with hydroxy, cyano, CO₂H or C(O)NH₂; R⁵ ishydrogen, C₁-C₄alkyl, amino, mono- and di-C₁-C₄alkylamino,C₃-C₆cycloalkylamino or —N(H)C(O)C₁-C₄alkyl, where each alkyl orcycloalkyl is optionally substituted with hydroxy; R⁶ is hydrogen,C₁-C₄alkyl, haloC₁-C₆alkyl or halogen; R⁷ is hydrogen or C₁-C₄alkyl; R⁸is C₁-C₆alkyl, NR^(8d)R^(8e), C₃-C₇cycloalkyl or haloC₁-C₆alkyl, whereineach alkyl, cycloalkyl or haloalkyl is optionally substituted withhydroxy, CO₂H, CO₂C₁-C₆alkyl or C(O)NH₂; or R⁸ is a group of theformula:

wherein p is 1 or 2; R^(8a) is hydrogen, C₁-C₆alkyl or phenylsubstituted with halogen; R^(8b) is hydrogen, halogen, C₁-C₄alkyl,haloC₁-C₄alkyl, C₁-C₄alkoxy, C₃-C₅cycloalkyl, cyano, amino orSO₂C₁-C₆alkyl;

R^(8c) is hydrogen, halogen, hydroxy or C₁-C₆alkyl; or CR^(8b)R^(8c),taken in combination form a spirocyclic 3 to 6 member carboxycle or a 4to 6 member heterocycle having a ring heteroatom selected from N, O orS, which spirocycle is optionally substituted with hydroxy, C₁-C₄alkyl,haloC₁-C₄alkyl or C₁-C₄alkoxy; R^(8d) is hydrogen, C₁-C₆alkyl,haloC₁-C₆alkyl, C₃-C₇cycloalkyl, 4 to 7 member heterocycloalkyl having 1ring heteroatoms selected from N, O or S and 0 or 1 additional ringnitrogen atoms, which heterocycloalkyl is optionally substituted with 1or 2 substituents independently selected from hydroxy, halogen, oxo,C₁-C₆alkyl, or C₁-C₆alkoxy; R^(8e) is hydrogen or C₁-C₆alkyl; orNR^(8d)R^(8e), taken in combination, form a 4 to 7 memberheterocycloalkyl optionally comprising an additional ring heteroatomselected from N, O or S, which heterocycloalkyl is optionallysubstituted with 1 or 2 substituents independently selected fromhydroxy, halogen, oxo, C₁-C₆alkyl, C₁-C₆alkoxy and heteroaryl, whichheteroaryl has 5 or 6 ring atoms and has one ring heteroatom selectedfrom N, O and S and 0 or 1 additional ring nitrogen atom, orNR^(8d)R^(8e), taken in combination, forms a 5 or 6 member heteroaryl,which heteroaryl optionally comprises 1 additional ring heteroatomselected from N, O and S.

In a fourteenth embodiment, the invention provides compounds of any oneof the first to thirteenth embodiment in which Q is

wherein Z² is CH or N; Z³ is CH or N; R⁸ is C₁-C₆alkyl, C₃-C₇cycloalkylor haloC₁-C₆alkyl; or R⁸ is a group of the formula:

wherein R^(8b) is halogen, C₁-C₄alkyl, haloC₁-C₄alkyl, C₁-C₄alkoxy,C₃-C₅cycloalkyl, cyano, or amino; R^(8c) is hydrogen, halogen, hydroxyor C₁-C₆alkyl; or CR^(8b)R^(8c), taken in combination, forms aspirocyclic 3 to 4 member carboxycle or a 4 or 5 member heterocyclehaving a ring heteroatom selected from N, O and S, which spirocycle isoptionally substituted with hydroxy, C₁-C₄alkyl, haloC₁-C₄alkyl orC₁-C₄alkoxy. In certain aspects of the fourteenth embodiment, Q is

wherein Z² is N; Z³ is CH; and R⁸ is C₁-C₆alkyl. In certain aspects ofthe fourteenth embodiment, Q is

wherein Z² is CH; Z³ is N; and R⁸ is C₁-C₆alkyl. In certain aspects ofthe fourteenth embodiment, Q is

wherein Z² is N; Z³ is CH; R⁸ is C₁-C₆alkyl; R^(13a) is hydrogen; andR¹³ and R¹⁴, taken in combination with the interposed C and N atoms,form a pyrrolidine ring, wherein the pyrrolidine ring is fused to acyclopropyl ring and the pyrrolidine ring is unsubstituted. In certainaspects of the fourteenth embodiment, Q is

wherein Z² is CH; Z³ is N; R⁸ is C₁-C₆alkyl; R^(13a) is hydrogen; andR¹³ and R¹⁴, taken in combination with the interposed C and N atoms,form a pyrrolidine ring, wherein the pyrrolidine ring is fused to acyclopropyl ring and the pyrrolidine ring is unsubstituted. In certainaspects of the fourteenth embodiment, Q is

wherein Z² is N; Z³ is CH; R⁸ is C₁-C₆alkyl; X¹ is CR²; R² is halogen;X² and X⁵ are each CH; X³ is CR^(3a); R^(3a) is halogen ortrifluoromethyl; X⁴ is CR³; and R³ is halogen. In certain aspects of thefourteenth embodiment, Q is

wherein Z² is CH; Z³ is N; R⁸ is C₁-C₆alkyl; X¹ is CR²; R² is halogen;X² and X⁵ are each CH; X³ is CR^(3a); R^(3a) is halogen ortrifluoromethyl; X⁴ is CR³; and R³ is halogen. In certain aspects of thefourteenth embodiment, Q is

wherein Z² is N; Z³ is CH; R⁸ is C₁-C₆alkyl; and R¹ is cyclopropyl. Incertain aspects of the fourteenth embodiment, Q is

wherein Z² is CH; Z³ is N; R⁸ is C₁-C₆alkyl; and R¹ is cyclopropyl.

In a fifteenth embodiment, the invention provides compounds of any oneof the first to third embodiment in which the compound is a compoundaccording to the Formula (II):

whereinR¹ is selected from the group consisting of hydrogen, C₁-C₆alkyl, haloC₁-C₆alkyl, C₃-C₇cycloalkyl, C₃-C₇cycloalkylmethyl, and 4 to 6 memberheterocycloalkyl having a ring heteroatom selected from N and O, whichheterocycloalkyl is optionally substituted with 1 or 2 groups selectedfrom oxo and hydroxy, and wherein the alkyl or cycloalkyl is optionallysubstituted with hydroxy;R² is hydrogen, halogen, C₁-C₄alkyl or C₁-C₄alkoxy;R³ is halogen, C₁-C₄alkyl, haloC₁-C₄alkyl or SF₅;X⁴ is CR³ or N;R³ is hydrogen or halogen;Z² is CH or N;Z³ is CH or N;R⁸ is C₁-C₆alkyl, C₃-C₇cycloalkyl or haloC₁-C₆alkyl; orR⁸ is a group of the formula:

whereinR^(8b) is halogen, C₁-C₄alkyl, haloC₁-C₄alkyl, C₁-C₄alkoxy,C₃-C₅cycloalkyl, cyano, or amino; R^(8c) is hydrogen, halogen, hydroxyor C₁-C₆alkyl; orCR^(8b)R^(8c), taken in combination form a spirocyclic 3 to 4 membercarboxycle or a 4 or 5 member heterocycle having a ring heteroatomselected from N, O or S, which spirocycle is optionally substituted withhydroxy, C₁-C₄alkyl, haloC₁-C₄alkyl or C₁-C₄alkoxy;W is a bond, CH₂, CH₂CH₂ or CH₂O, where the oxygen is adjacent toCR^(15a)R^(15b);R^(15a) and R^(15b) are independently selected from the group consistingof hydrogen, halogen, hydroxy, C₁-C₄alkyl, hydroxyC₁-C₄alkyl,C₁-C₄alkoxy and C₃-C₆cycloalkyl; orR^(15a) and R^(15b), taken in combination with the carbon atom to whichthey are attached, form a spirocyclic cyclopropyl ring;R¹⁶ is hydrogen; orR^(15a) and R¹⁶, taken in combination with the carbon atoms to whichthey are attached, form a fused cyclopropyl ring.

In certain aspects of the fifteenth embodiment, compounds of Formula(II) are provided according to Formula (IIa):

where variables X⁴, Z², Z³, R¹, R², R^(3a), R⁸, R¹⁵, R^(15a) and R¹⁶ areas defined in the fifteenth embodiment. In some aspects of the fifteenthembodiment, X⁴ is CR³; R³ is hydrogen or halogen; W is CH₂; Z² is N; andZ³ is CH. In certain aspects of the compounds of Formula (IIa), R⁸ isC₁-C₆alkyl. In certain aspects of the compounds of Formula (IIa), R¹ isC₃-C₇cycloalkyl. In certain aspects of the compounds of Formula (IIa),R⁸ is C₁-C₆alkyl and R¹ is C₃-C₇cycloalkyl. In certain aspects of thecompounds of Formula (IIa), R¹ is C₃-C₇cycloalkyl; R² is halogen; R^(3a)is halogen or haloC₁-C₄alkyl; X⁴ is CR³; R³ is halogen; Z² is N; Z³ isCH; and R⁸ is C₁-C₆alkyl.

In certain other aspects of the fifteenth embodiment, compounds ofFormula (II) are provided according to Formula (IIb):

where variables X⁴, Z², Z³, R¹, R², R^(3a) and R⁸ are as defined in thefifteenth embodiment. In certain aspects of the compounds of Formula(IIb), Z² is N and Z³ is CH. In certain aspects of the compounds ofFormula (IIb), Z² is CH and Z³ is N. In certain aspects of the compoundsof Formula (IIb), R⁸ is C₁-C₆alkyl. In certain aspects of the compoundsof Formula (IIb), R¹ is C₃-C₇cycloalkyl. In certain aspects of thecompounds of Formula (IIb), R⁸ is C₁-C₆alkyl and R¹ is C₃-C₇cycloalkyl.In certain aspects of the compounds of Formula (IIb), R¹ isC₃-C₇cycloalkyl; R² is halogen; R^(3a) is halogen or haloC₁-C₄alkyl; X⁴is CR³; R³ is halogen; Z² is N; Z³ is CH; and R⁸ is C₁-C₆alkyl.

In a sixteenth embodiment, the invention provides compounds of any oneof the first to twelfth embodiment in which Q is

wherein A is oxygen, N(H), or CHR¹¹; R⁸ is C₁-C₆alkyl, NR^(8d)R^(8e),C₃-C₇cycloalkyl, haloC₁-C₆alkyl or benzyl, and wherein each alkyl,cycloalkyl or haloalkyl is optionally substituted with hydroxy, CO₂H,CO₂C₁-C₆alkyl or C(O)NH₂; or R⁸ is a group of the formula:

wherein R^(8b) is hydrogen, C₁-C₄alkyl, halo C₁-C₄alkyl, C₁-C₄alkoxy,C₃-C₆cycloalkyl, cyano, or amino; R^(8c) is hydrogen, hydroxy orC₁-C₆alkyl; R^(8d) is hydrogen, C₁-C₆alkyl, haloC₁-C₆alkyl, orC₃-C₇cycloalkyl; R^(8e) is hydrogen or C₁-C₆alkyl; R⁹ is hydrogen; R¹⁰is hydrogen; or R⁹ and R¹⁰, taken in combination, form a divalentmethylene bridge; and R¹¹ is hydrogen or C₁-C₆alkyl.

In a seventeenth embodiment, the invention provides compounds of any oneof the first to third embodiment in which the compound is a compoundaccording to the formula:

whereinR¹ is selected from the group consisting of hydrogen, C₁-C₆alkyl, haloC₁-C₆alkyl, C₃-C₇cycloalkyl, C₃-C₇cycloalkylmethyl, and 4 to 6 memberheterocycloalkyl having a ring heteroatom selected from N and O, whichheterocycloalkyl is optionally substituted with 1 or 2 groups selectedfrom oxo and hydroxy, and wherein the alkyl or cycloalkyl is optionallysubstituted with hydroxy;R² is hydrogen, halogen, C₁-C₄alkyl or C₁-C₄alkoxy;R^(3a) is halogen, C₁-C₄alkyl, haloC₁-C₄alkyl or SF₅;X⁴ is CR³ or N;R³ is hydrogen or halogen;Z² is CH or N;Z³ is CH or N;R⁸ is C₁-C₆alkyl, C₃-C₇cycloalkyl or haloC₁-C₆alkyl; orR⁸ is a group of the formula:

R^(8b) is halogen, C₁-C₄alkyl, haloC₁-C₄alkyl, C₁-C₄alkoxy,C₃-C₅cycloalkyl, cyano, or amino;R^(8c) is hydrogen, halogen, hydroxy or C₁-C₆alkyl; orCR^(8b)R^(8c), taken in combination, forms a spirocyclic 3 to 4 membercarboxycle or a 4 or 5 member heterocycle having a ring heteroatomselected from N, O and S, which spirocycle is optionally substitutedwith hydroxy, C₁-C₄alkyl, haloC₁-C₄alkyl or C₁-C₄alkoxy; W is a bond,CH₂, CH₂CH₂ or CH₂O, where the oxygen is adjacent to CR^(15a)R^(15b);R^(15a) and R^(15b) are independently selected from the group consistingof hydrogen, halogen, hydroxy, C₁-C₄alkyl, hydroxyC₁-C₄alkyl,C₁-C₄alkoxy and C₃-C₆cycloalkyl; orR^(15a) and R^(15b), taken in combination with the carbon atom to whichthey are attached, form a spirocyclic cyclopropyl ring; andR¹⁶ is hydrogen; orR^(15a) and R¹⁶, taken in combination with the carbon atoms to whichthey are attached, form a fused cyclopropyl ring, and R^(15b) isselected from the group consisting of hydrogen, halogen, hydroxy,C₁-C₄alkyl, hydroxyC₁-C₄alkyl, C₁-C₄alkoxy and C₃-C₆cycloalkyl.

In certain aspects of the seventeenth embodiment, compounds of Formula(III) are provided according to Formula (IIIa):

where variables A, W, X⁴, R¹, R², R^(3a), R⁹, R¹⁰, R¹², R¹⁵, R^(15a) andR¹⁶ are as defined in the seventeenth embodiment.

In an Eighteenth Embodiment, the Invention Provides Compounds as Recitedin the Below Table A, or a Pharmaceutically Acceptable Salt Thereof:

TABLE A

-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-2-cyclopropyl-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   N—((R)-(4-chloro-2-fluorophenyl)(cyclopropyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   (1R,2R,5S)-3-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-4,4-difluoro-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-3,3,3-trifluoro-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-4,4-difluoro-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N—((R)-cyclopropyl(4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   (2R)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-(3,4-dichlorophenyl)ethyl)-2-piperidinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-2-cyclopropyl-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   (6R)-5-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-5-azaspiro[2.4]heptane-6-carboxamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)-5-fluorophenyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   (2R)—N-((1R)-1-(4-chlorophenyl)ethyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-2-piperidinecarboxamide;-   (3R)-4-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-3-morpholinecarboxamide;-   N-(4-chloro-2,5-difluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(3,4-dichlorobenzyl)-D-prolinamide;-   (1R,3R,5R)-2-(2-(ethylamino)-5-methylbenzoyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-((1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4,4-difluoro-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(2-(cyclopropylamino)-5-(methylsulfonyl)benzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   (2R)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-piperidinecarboxamide;-   (2S)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-piperidinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-3,3,3-trifluoro-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N—((R)-cyclopropyl(4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1S)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)-2-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4R)—N—((R)-(4-chloro-2,5-difluorophenyl)    (3-oxetanyl)methyl)-1-(2-(ethylamino)-5-methylbenzoyl)-4-hydroxy-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-3-hydroxy-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N—((S)-cyclopropyl(4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   N-(3-chloro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)-2-(2-(cyclobutylamino)-5-(methylsulfonyl)benzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-(4-chlorobenzyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D-prolinamide;    1-(2-(cyclobutylamino)-5-(methylsulfonyl)benzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-3-methyl-1-(4-(trifluoromethyl)phenyl)butyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-(2-fluoro-4-methylphenyl)ethyl)-D-prolinamide;-   N—((S)-3-azetidinyl(4-chloro-2,5-difluorophenyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N-((1R)-1-(4-chloro-2,5-difluorophenyl)ethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-(ethylamino)-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-(4-chloro-3-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N—((R)-cyclopropyl(4-(pentafluoro-lambda˜6˜-sulfanyl)phenyl)methyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)-5-fluorophenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (3R)-4-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-3-morpholinecarboxamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-(3,5-difluorobenzyl)-D-prolinamide;    (4S)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-fluoro-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-((1S)-1-(4-chlorophenyl)-2-hydroxyethyl)-1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide;    1-(((3S)-1-((cis-3-cyanocyclobutyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methyl-4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(5-(methylsulfonyl)-2-(2-propanylamino)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-(2-chloro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N-(4-chloro-3-fluorobenzyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D-prolinamide;-   (2R)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2    piperidinecarboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-3-methyl-1-(4-(trifluoromethyl)phenyl)butyl)-D-prolinamide;-   N-((1R)-1-(4-chloro-3-fluorophenyl)ethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N-(4-chloro-2-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N-((1R)-1-(4-chlorophenyl)ethyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-methyl-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(2-fluoro-4-methylbenzyl)-D-prolinamide;-   1-(((3R)-1-((3-cyano-1-azetidinyl)sulfonyl)-5,5-difluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-5,5-difluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-((1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-(ethylamino)-5-(methylsulfonyl)benzoyl)-D-prolinamide;-   methyl    ((3-(((1R,3R,5R)-3-(((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)carbamoy)-2-azabicyclo[3.1.0]hexan-2-yl)carbonyl)phenyl)sulfonyl)acetate;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(5-(methylsulfonyl)-2-(2-propanylamino)benzoyl)-D-prolinamide;-   1-(((3S,4R)-1-((3-cyano-1-azetidinyl)sulfonyl)-4-methyl-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-(3-fluoro-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1S)-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   (2R)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1S)-1-(3,4-dichlorophenyl)ethyl)-2-piperidinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-4-methylbenzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   (2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(propylsulfonyl)benzoyl)-2-piperidinecarboxamide;-   (1R,2R,5S)-3-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,4-dichlorobenzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-(cyclopropylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R)-2-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-isoindole-1-carboxamide;-   (1S)-2-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-isoindole-1-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-(3-((2-hydroxyethyl)sulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-4,4-difluoro-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-D-prolinamide;-   (2R)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-azepanecarboxamide;-   (2S)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-azepanecarboxamide;-   N-((1R)-1-(4-chlorophenyl)-2-methoxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N-((1S)-1-(4-chlorophenyl)-2-methoxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-methylphenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,4-dichlorobenzyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-(2,3,5-trifluorobenzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-((2-methyl-2-propanyl)amino)-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(difluoromethyl)benzyl)-D-prolinamide;-   1-(((1R,4R,6R)-2-((3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[2.2.1]hept-6-yl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)-D-prolinamide;-   N-((1R)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-methylbenzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N—((S)-cyclopropyl(4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-(ethylamino)-5-methylbenzoyl)-D-prolinamide;-   (3R)-4-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-3-morpholinecarboxamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (3-oxetanyl)methyl)-1-(2-(ethylamino)-5-methylbenzoyl)-4-hydroxy-D-prolinamide;-   N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;    (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-((2-hydroxyethyl)sulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (2R)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2-piperidinecarboxamide;-   N—((R)-(4-chloro-3-fluorophenyl)    (cyclopropyl)methyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(trifluoromethyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N—((R)-cyclopropyl(4-(pentafluoro-lambda˜6˜-sulfanyl)phenyl)methyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-((2-hydroxyethyl)amino)-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-(4-chloro-2-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-(4-(difluoromethyl)phenyl)ethyl)-D-prolinamide;-   3-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-(((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)benzamide;-   (4R)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-4-fluoro-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-((1-((3-cyano-1-azetidinyl)sulfonyl)-1H-pyrazol-4-yl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-1-(3,5-difluorophenyl)propyl)-D-prolinamide;-   (2R)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-1-((6-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-piperidinecarboxamide;-   (4R)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-4-hydroxy-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-(trifluoromethyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)-2-(3-(ethylsulfonyl)benzoyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-(3-(methylsulfonyl)benzoyl)-1,3-thiazolidine-4-carboxamide;-   N-(3-chloro-4-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-D-prolinamide;-   N—((R)-(4-chlorophenyl)((2R)-tetrahydro-2-furanyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide    &    N—((R)-(4-chlorophenyl)((2S)-tetrahydro-2-furanyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide    &    N—((S)-(4-chlorophenyl)((2R)-tetrahydro-2-furanyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide    &    N—((S)-(4-chlorophenyl)((2S)-tetrahydro-2-furanyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;    (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-(ethylsulfonyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   N-((1R)-1-(4-chlorophenyl)ethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((2-(trifluoromethyl)-5-pyrimidinyl)methyl)-D-prolinamide;-   N-(4-chloro-3-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-(cyclopropylsulfonyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-sulfamoylbenzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-(3-methyl-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-((2-((3-cyano-1-azetidinyl)sulfonyl)-4-pyridinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-4,4-difluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methyl-3-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(3-(dimethylsulfamoyl)benzoyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-(methylamino)-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-((1R)-1-(4-chlorophenyl)ethyl)-1-(((3S)-1-((3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-(1H-1,2,3-triazol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N-(3-chloro-2-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,4,5-trifluorobenzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-((2-hydroxyethyl)amino)-5-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(3-fluoro-4-methylphenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(3-fluoro-4-methylphenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(fluoromethyl)benzyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1S)-2-hydroxy-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   (2R)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-1-((4-(methylsulfonyl)-2-pyridinyl)carbonyl)-2-piperidinecarboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(ethylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclobutyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-(4-chlorobenzyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-methyl-D-prolinamide;-   N-(4-chlorobenzyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-methyl-L-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(cyclopropylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-(4-chlorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1S)-1-(3,5-difluorophenyl)propyl)-D-prolinamide;-   1-(((3S)-1-(((2R)-2-(3-fluorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-(((2S)-2-(3-fluorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   3-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-(((1S)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)benzamide;-   1-((1-((3-cyano-1-azetidinyl)sulfonyl)-4-fluoro-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-((1S)-1-(4-chlorophenyl)-2-hydroxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3R,4S)-1-((3-cyano-1-azetidinyl)sulfonyl)-4-methyl-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S,4R)-1-((3-cyano-1-azetidinyl)sulfonyl)-4-methyl-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((1R,4R,6R)-2-((3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[2.2.1]hept-6-yl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (4S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   N-(4-chloro-3-fluorobenzyl)-1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-D-prolinamide;-   (3R)-4-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-3-morpholinecarboxamide;-   N-(4-chloro-2-methoxybenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (1S,2R,5R)-3-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(4-(difluoromethyl)-2,5-difluorophenyl)methyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-(3-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-(((2R)-2-(3-bromophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-(((2S)-2-(3-bromophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-methylbenzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-fluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide    or    1-(((3R)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-fluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)-2-(3-(1-carbamoylcyclopropyl)benzoyl)-N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(3-(dimethylsulfamoyl)benzoyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-((2-methyl-2-propanyl)amino)-5-(methylsulfonyl)benzoyl)-D-prolinamide;-   N-(4-chloro-2-fluorobenzyl)-1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-O-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((1R,4R,6R)-2-((3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[2.2.1]hept-6-yl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((1S,4S,6S)-2-((3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[2.2.1]hept-6-yl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-(3-chlorobenzyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D-prolinamide;-   N-(2-chloro-4-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-(((3S)-3-cyano-1-pyrrolidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(3-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (2R)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-1-(3-sulfamoylbenzoyl)-2-piperidinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   1-(((3S)-1-((3-ethynyl-3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(4-(difluoromethyl)-2,5-difluorophenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyclopropyl-3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-(methylsulfonyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-(1H-1,2,3-triazol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-1-(3,5-difluorophenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3-dichlorobenzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2-fluorophenyl)(3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-((2R)-1,1,1-trifluoro-2-hydroxy-2-propanyl)benzoyl)-2-piperidinecarboxamide;-   (2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-((2S)-1,1,1-trifluoro-2-hydroxy-2-propanyl)benzoyl)-2-piperidinecarboxamide;-   (3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-N-((2R)-1-(((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)amino)-1-oxo-2-propanyl)-N-methyl-3-piperidinecarboxamide;-   1-(((3S)-1-((3-((4-chlorobenzyl)oxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(cyclopropylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(ethylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-(3-(2-methyl-2-propanyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-1-((6-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   (4R)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-fluoro-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)-2-(2-(ethylamino)benzoyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)    (3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)-2-(3-fluoro-5-(methylsulfonyl)benzoyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,4-difluorobenzyl)-D-prolinamide;-   N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-1-((4-(methylsulfonyl)-2-pyridinyl)carbonyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(cyclopropylsulfonyl)benzoyl)-D-prolinamide;-   N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-1-(3-sulfamoylbenzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   3-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-((4-(trifluoromethyl)benzyl)amino)ethyl)benzamide;-   1-(((3S)-1-((3-(1,2-oxazol-3-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-(methylamino)-5-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-D-prolinamide;-   (1R,3R,5R)-2-((5-(cyclobutylamino)-2-methyl-4-pyridinyl)carbonyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((4-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-((3-((3,3-dimethyl-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclobutyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (3S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-3-(trifluoromethyl)-L-prolinamide;-   1-(((3S)-1-((3-(2-fluoroethoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-(4-chloro-3-fluorobenzyl)-1-(3-((3,3-difluoro-1-azetidinyl)sulfonyl)benzoyl)-D-prolinamide;-   1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (4R)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-hydroxy-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (3R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-3-(trifluoromethyl)-D-prolinamide;-   (3S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-3-(trifluoromethyl)-L-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-4-methoxy-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-4-methoxy-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-methylbenzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)((3R)-5-oxo-3-pyrrolidinyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(3,5-difluorophenyl)propyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(1-(cyclopropylsulfonyl)-3-fluoro-3-azetidinyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(difluoromethyl)phenyl)ethyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-((2-hydroxyethyl)sulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-cyanobenzyl)-D-prolinamide;-   (4S)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-4-hydroxy-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(trifluoromethyl)benzoyl)-D-prolinamide;-   (2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2-piperidinecarboxamide;-   N-((1R)-1-(4-chloro-2-fluorophenyl)ethyl)-1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-D-prolinamide;-   N—((R)-(4-chloro-3-fluorophenyl)    (3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;    1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,4-dimethylbenzyl)-D-prolinamide;-   1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(3,4-dichlorobenzyl)-D-prolinamide;-   1-((3-((3-methoxy-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-((1R)-1-(4-chloro-3-fluorophenyl)propyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide;-   N-((6-chloro-3-pyridinyl)methyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(difluoromethyl)benzyl)-D-prolinamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-4-fluoro-1-((6-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)-2-(3-(1-amino-2-methyl-1-oxo-2-propanyl)benzoyl)-N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-3-fluorophenyl)(3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (2R)—N-((1S)-1-(4-chlorophenyl)ethyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-2-piperidinecarboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((2-(difluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-(4-chlorophenyl)(phenyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide    &    N—((S)-(4-chlorophenyl)(phenyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-4-fluoro-1-((4-(methylsulfonyl)-2-pyridinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((2S,3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-2-methyl-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-(3-chloro-4-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (4S)-4-fluoro-N—((R)-(3-fluoro-4-(trifluoromethyl)phenyl)    (3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-(difluoromethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)-2-(3-(ethylsulfonyl)benzoyl)-N—((R)-3-oxetanyl(4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R,3R)-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R,3S)-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S,3R)-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S,3S)-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(((3S)-1-(methylsulfonyl)-3-piperidinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-3,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-4-fluoro-1-(3-sulfamoylbenzoyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-((2,2,2-trifluoroethyl)sulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-cyclopropylbenzyl)-D-prolinamide;-   N-(2-chloro-4-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-methylphenyl)ethyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(3-fluoro-1-(methylsulfonyl)-3-azetidinyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,5-difluorobenzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-2-methylbenzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((4-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-(4-chloro-2-fluorobenzyl)-1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-D-prolinamide;-   N-((1R)-1-(4-chlorophenyl)ethyl)-1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-D-prolinamide;-   (2R)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-piperidinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   (4R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-methyl-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((2-(cyclopropylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-(difluoromethyl)-3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-D-prolinamide;-   N-((1R)-2-(((1R)-1-(4-chlorophenyl)ethyl)amino)-1-methyl-2-oxoethyl)-3-((3-cyano-1-azetidinyl)sulfonyl)-N-methylbenzamide;-   N-((1R)-2-(((1S)-1-(4-chlorophenyl)ethyl)amino)-1-methyl-2-oxoethyl)-3-((3-cyano-1-azetidinyl)sulfonyl)-N-methylbenzamide;-   (2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-N-((2R)-1-(((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)amino)-1-oxo-2-propanyl)-N-methyl-2-morpholinecarboxamide;-   (2R)—N—((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2-piperidinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(3,4-difluorophenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-(((2R)-2-(2-fluorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-(((2S)-2-(2-fluorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-(4-chloro-3-fluorobenzyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide;-   N—((R)-(4-chloro-2-fluorophenyl)    (3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   N-((1R)-1-(4-chlorophenyl)-2-hydroxyethyl)-1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-D-prolinamide;-   ((3-(((1R,3R,5R)-3-(((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)carbonyl)phenyl)sulfonyl)acetic    acid;-   (1R,3R,5R)—N—((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-((1S)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-methoxy-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(cyclopropylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-(2,2-difluoroethoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (6R)-5-((3-(5-azaspiro[2.3]hex-5-ylsulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-5-azaspiro[2.4]heptane-6-carboxamide;-   N-(3-chloro-5-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(3-(methyl(2-propanyl)sulfamoyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((S)-(4-chloro-2,5-difluorophenyl)(1-hydroxycyclopropyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (3S)—N-((2R)-1-(((1R)-1-(4-chloro-2-fluorophenyl)ethyl)amino)-1-oxo-2-propanyl)-1-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-3-piperidinecarboxamide;-   (2R)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-1-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-piperidinecarboxamide;-   1-(((3S)-1-(((3R)-3-cyano-1-pyrrolidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4,4-difluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   N-((1R)-1-(2,4-difluorophenyl)ethyl)-1-(((3S)-1-((3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzoyl)-2-piperidinecarboxamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-(3-methyl-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R)-2-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydro-1-isoquinolinecarboxamide;-   (1S)-2-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydro-1-isoquinolinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2,4-difluorophenyl)ethyl)-D-prolinamide;-   (1R,3R,5R)-2-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-3-fluoro-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   (3R)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-4-(3-(methylsulfonyl)benzoyl)-3-morpholinecarboxamide;-   1-((3-(2-oxa-6-azaspiro[3.3]hept-6-ylsulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-((1S)-1-(4-chlorophenyl)ethyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D-prolinamide;-   N-((1R)-2-(((1S)-1-(4-chlorophenyl)ethyl)amino)-1-methyl-2-oxoethyl)-3-((3-cyano-1-azetidinyl)sulfonyl)-N-methylbenzamide;-   N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-hydroxy-3-(2-propanyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N-(4-chloro-3-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(3-fluoro-4-methylbenzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-3-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,4-dimethylbenzyl)-D-prolinamide;-   N-((1R)-2-((4-chlorobenzyl)amino)-1-methyl-2-oxoethyl)-3-((3-cyano-1-azetidinyl)sulfonyl)-N-methylbenzamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(pentafluorobenzyl)-D-prolinamide;-   1-(((3S)-1-(((2R)-2-phenyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-(((2S)-2-phenyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,2R,5S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-3-(3-sulfamoylbenzoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   3-((3-cyano-1-azetidinyl)sulfonyl)-N-((1R)-2-((3,4-dichlorobenzyl)amino)-1-methyl-2-oxoethyl)-N-methylbenzamide;-   (4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-1,3-thiazolidine-4-carboxamide;-   1-(((3S)-1-((3-(difluoromethoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2-fluorophenyl)(cyclopropyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(2-amino-5-(methylsulfonyl)benzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   methyl    N-methyl-N-((3-(((2R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)-1-pyrrolidinyl)carbonyl)phenyl)sulfonyl)glycinate;-   (2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-((1R)-2,2,2-trifluoro-1-hydroxyethyl)benzoyl)-2-piperidinecarboxamide;-   (2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-((1S)-2,2,2-trifluoro-1-hydroxyethyl)benzoyl)-2-piperidinecarboxamide;-   (1R,3R,5R)-2-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)-2-(3-(1-carbamoylcyclopropyl)benzoyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-((3-(5-azaspiro[2.3]hex-5-ylsulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-(2-(2,2,2-trifluoroacetamido)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4S)—N—((R)-(4-chloro-2-fluorophenyl)(3-oxetanyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-(trifluoromethyl)benzyl)-D-prolinamide;-   (4R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-(difluoromethyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (2R)-1-((3-((trans-3-cyanocyclobutyl)sulfonyl)phenyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-2-piperidinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3,5-trifluorobenzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((3R)-4,6-difluoro-2,3-dihydro-1-benzofuran-3-yl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((3S)-4,6-difluoro-2,3-dihydro-1-benzofuran-3-yl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-methyl-5-(trifluoromethyl)benzyl)-D-prolinamide;-   (2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-sulfamoylbenzoyl)-2-piperidinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,4-difluorobenzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-methyl-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide;-   (4S)—N—((R)-(4-chloro-3-fluorophenyl)(3-oxetanyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)-2-(3-cyanobenzoyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-(1H-pyrrol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(3-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)benzoyl)-D-prolinamide;-   1-(3-cyclopropylbenzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   1-(3-(methylsulfonyl)benzoyl)-N—((R)-3-oxetanyl(4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   1-(((3S)-1-((3-hydroxy-3-phenyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)-2-(2-acetamidobenzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)-2-(3-(methylsulfonyl)benzoyl)-N—((R)-3-oxetanyl(4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-((5-chloro-1,3-thiazol-2-yl)methyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D-prolinamide;-   (2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2,3-dihydro-1H-pyrrole-2-carboxamide;-   1-(3-chlorobenzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-5-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-(trifluoromethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-2-methylbenzyl)-D-prolinamide;-   (1R,3R,5R)-2-(3-(ethylsulfonyl)benzoyl)-N—((S)-(2-fluoro-4-(trifluoromethyl)phenyl)(1-hydroxycyclopropyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(ethylamino)-2-methyl-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-(4-(trifluoromethyl)benzyl)-1-(((3S)-1-(((3S)-3-(trifluoromethyl)-1-pyrrolidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(3-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-2-hydroxy-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-methoxy-4-methylbenzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-2-methoxy-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-2-methoxy-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((2-(ethylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,5-dichlorobenzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(3,5-difluorophenyl)ethyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,2R,5S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-3-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,5-difluorobenzyl)-D-prolinamide;-   (1R,3R,5R)—N-((1S,2S)-1-(4-chloro-2,5-difluorophenyl)-2-hydroxypropyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-(2-chlorobenzyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D-prolinamide;-   (4R)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-4-hydroxy-1-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-(3-chlorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (4R)—N—((R)-(4-chloro-2,5-difluorophenyl)    (3-oxetanyl)methyl)-4-hydroxy-1-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((2-(trifluoromethyl)-5-pyrimidinyl)methyl)-D-prolinamide;-   (2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2,5-dihydro-1H-pyrrole-2-carboxamide;-   (2R,4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chlorophenyl)(3-oxetanyl)methyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-2-hydroxy-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   (1R,3R,5R)—N-((1S,2S)-1-(4-chloro-2,5-difluorophenyl)-2-hydroxypropyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-(3-chloro-2-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (1R,2R,5S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-(3-(methylsulfonyl)benzoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   N—((S)-(4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((4-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-D-prolinamide;-   (4S)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-4-fluoro-N-((1R)-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   (1R,3R,5R)-2-(3-(2-cyano-2-propanyl)benzoyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(fluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(2-propanyl)benzoyl)-D-prolinamide;-   (3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-(((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)-3-piperidinecarboxamide;-   (4S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methoxy-4-methylbenzyl)-D-prolinamide;-   N-(2-chloro-3-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (2S)—N-((2R)-1-(((1R)-1-(4-chloro-2-fluorophenyl)ethyl)amino)-1-oxo-2-propanyl)-4-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-2-morpholinecarboxamide;-   (2R)—N-((6-chloro-3-pyridinyl)methyl)-1-((3-((trans-3-cyanocyclobutyl)sulfonyl)phenyl)carbonyl)-2-piperidinecarboxamide;-   N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-1-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(3-fluoro-1-(methylsulfonyl)-3-azetidinyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3,4,6-tetrafluorobenzyl)-D-prolinamide;-   1-(((3S)-1-((3-(4-chlorophenoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((cis-3-carbamoylcyclobutyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-(4-chloro-3-fluorophenyl)    (cyclopropyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (4S)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-fluoro-N-(3-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   N-(3,5-difluorobenzyl)-1-(((3S)-1-((3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (4S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   (3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-((4-(trifluoromethyl)benzyl)amino)ethyl)-3-piperidinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3-dimethylbenzyl)-D-prolinamide;-   1-((3-(5-azaspiro[2.3]hex-5-ylsulfonyl)phenyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(difluoromethoxy)benzyl)-D-prolinamide;-   1-(3-(dimethylsulfamoyl)benzoyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluorobenzyl)-D-prolinamide;-   N-(3-chlorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-3-methylbenzyl)-D-prolinamide;-   N-(2-chloro-5-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N-((1R)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;-   N-(3-chloro-5-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(4-(methylsulfonyl)picolinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-3,5-dimethylbenzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4,4-difluoro-1-(3-sulfamoylbenzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-cyclopropylbenzyl)-D-prolinamide;-   (3R)-4-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(difluoromethyl)benzyl)-3-morpholinecarboxamide;-   N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(3-((3-hydroxy-1-azetidinyl)sulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyclopropyl-3-fluoro-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(3-fluoro-1-(3-oxetanylsulfonyl)-3-azetidinyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-methylphenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(4-methylphenyl)ethyl)-D-prolinamide;-   N-((1R)-1-(4-chloro-2,5-difluorophenyl)propyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(3-(benzylsulfonyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   3-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-((3-(trifluoromethyl)benzyl)amino)ethyl)benzamide;-   (1R,3R,5R)-2-(3-(1-cyanocyclopropyl)benzoyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-4-methoxybenzyl)-D-prolinamide;-   (1R,3R,5R)-2-((5-(cyclopropylamino)-2-methyl-4-pyridinyl)carbonyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(3-(dimethylsulfamoyl)benzoyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   (2R)-1-((3-((cis-3-cyanocyclobutyl)sulfonyl)phenyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-2-piperidinecarboxamide;-   (2R)-1-((3-((trans-3-cyanocyclobutyl)sulfonyl)phenyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-2-piperidinecarboxamide;-   1-((3-((3,3-difluoro-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-((1S)-1-(4-chloro-3-fluorophenyl)ethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-fluoro-3-phenyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-fluoro-5-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(3-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-hydroxy-3-(trifluoromethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(3,5-difluorophenyl)propyl)-D-prolinamide;-   1-(((3S)-1-((3-((4-fluorophenyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-pyrrolidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((4-cyclopropyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-(4-methyl-3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-(((3R)-2-oxo-3-azepanyl)sulfamoyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-(((3S)-2-oxo-3-azepanyl)sulfamoyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-((3-((4-methoxy-1-piperidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azaspiro[3.3]heptane-1-carboxamide;-   (3R,5R)-5-(((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)carbamoyl)-1-((2-(difluoromethyl)-4-pyridinyl)carbonyl)-3-pyrrolidinyl    2-(difluoromethyl)-4-pyridinecarboxylate;-   1-(((3S)-1-((3-(4-fluorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,2R,5S)-3-(3-(dimethylsulfamoyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   N—((R)-(4-chloro-2-fluorophenyl)    (cyclopropyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)-2-((2-(difluoromethyl)-4-pyridinyl)carbonyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (2R)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-indole-2-carboxamide;-   (2S)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-indole-2-carboxamide;-   1-(3-(methylsulfonyl)benzoyl)-N—((R)-((3R)-5-oxo-3-pyrrolidinyl)(4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   1-(((3S)-1-((3-cyclobutyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1S,2R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-(3-(methylsulfonyl)benzoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(3-(1-azetidinylsulfonyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((6-(trifluoromethyl)-4-pyrimidinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-4-fluoro-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-((trifluoroacetyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((6-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(cyclopropylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-methoxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (3R,5R)-5-(((R)-(4-chloro-2,5-difluorophenyl)    (3-oxetanyl)methyl)carbamoyl)-1-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-3-pyrrolidinyl    2-(trifluoromethyl)-4-pyridinecarboxylate;-   (4S)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-fluoro-N-((1R)-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluorobenzyl)-D-prolinamide;-   (1R,3R,5R)-2-(3-(1-amino-2-methyl-1-oxo-2-propanyl)benzoyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-5-methylbenzyl)-D-prolinamide;-   1-(((3S)-1-((3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((2-(trifluoromethyl)-4-pyrimidinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4R)—N—((R)-(4-chloro-2,5-difluorophenyl)    (3-oxetanyl)methyl)-1-((2-(difluoromethyl)-4-pyridinyl)carbonyl)-4-hydroxy-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4R)-3,4-dihydro-2H-chromen-4-yl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4S)-3,4-dihydro-2H-chromen-4-yl)-D-prolinamide;-   1-(((1R,4S,5R)-2-((3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[3.1.0]hex-4-yl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((1S,4R,5S)-2-((3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[3.1.0]hex-4-yl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((2-(2-propanyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((6-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   (4R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-hydroxy-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-((3-((cis-3-cyanocyclobutyl)sulfonyl)phenyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-D-prolinamide;-   1-((3-((trans-3-cyanocyclobutyl)sulfonyl)phenyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methy)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(5-fluoro-2-methylbenzyl)-D-prolinamide;-   1-(((3S)-1-((3-ethyl-3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-4-fluoro-1-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-D-prolinamide;-   N-((1R)-1-(4-chlorophenyl)ethyl)-1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-D-prolinamide;-   (1R,2R,5S)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-3-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   (1R,3R,5R)—N-((1R)-1-(4-chloro-2,5-difluorophenyl)ethyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3R)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-fluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide    or    1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-fluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)methyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3-difluorobenzyl)-D-prolinamide;-   1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-N-(3,5-difluorobenzyl)-D-prolinamide;-   methyl    cis-3-(((3S)-3-(((2R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)-1-pyrrolidinyl)carbonyl)-1-piperidinyl)sulfonyl)cyclobutanecarboxylate;-   methyl    trans-3-(((3S)-3-(((2R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)-1-pyrrolidinyl)carbonyl)-1-piperidinyl)sulfonyl)cyclobutanecarboxylate;-   (1R,3R,5R)—N—((S)-(2-fluoro-4-(trifluoromethyl)phenyl)((3R)-1-methyl-5-oxo-3-pyrrolidinyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((5-methyl-2-pyridinyl)methyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-(ethylamino)benzoyl)-D-prolinamide;-   (1R,3R,5R)-2-(3-(ethylsulfonyl)benzoyl)-N—((S)-(1-hydroxycyclobutyl)(4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2,5-difluorophenyl)-2,2-difluoroethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(2,5-difluorophenyl)-2,2-difluoroethyl)-D-prolinamide;-   (2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4,4-difluoro-1-(3-(methylsulfonyl)benzoyl)-2-piperidinecarboxamide    &    (2S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4,4-difluoro-1-(3-(methylsulfonyl)benzoyl)-2-piperidinecarboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((4-(methylsulfonyl)-2-pyridinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4S)-4-fluoro-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)    (3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((6-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(3-cyclobutylbenzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   (4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-sulfamoylbenzoyl)-D-prolinamide;-   N-(3-chloro-5-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(3-(1-carbamoylcyclopropyl)benzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   (1R,3R,5R)—N-((1R)-1-(4-chloro-2,5-difluorophenyl)ethyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-(trifluoromethoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-(pentyloxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (3R)-4-((3-(5-azaspiro[2.3]hex-5-ylsulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-3-morpholinecarboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3R)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-cyanophenyl)ethyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((5-((2-hydroxyethyl)amino)-2-methyl-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (2R)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-azetidinecarboxamide;-   (4R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-(3-(methylsulfonyl)benzoyl)-2-oxo-1,3-oxazolidine-4-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-methyl-3-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-((2-hydroxyethyl)amino)-2-methyl-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4S)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-N—((R)-3-oxetanyl(4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-((1R)-2,2,2-trifluoro-1-hydroxyethyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-((1S)-2,2,2-trifluoro-1-hydroxyethyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-(5-chloro-2-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(2-(3-cyano-1-azetidinyl)-5-(methylsulfonyl)benzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-cyanobenzyl)-D-prolinamide;-   (3R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-(3-(methylsulfonyl)benzoyl)-3-thiomorpholinecarboxamide;-   (3S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-(3-(methylsulfonyl)benzoyl)-3-thiomorpholinecarboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-(2,2,2-trifluoroacetamido)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-ethoxy-5-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((4-ethyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-((1R)-2,2,2-trifluoro-1-hydroxyethyl)benzoyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-((1S)-2,2,2-trifluoro-1-hydroxyethyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-methoxybenzyl)-D-prolinamide;-   N—((R)-3-azetidinyl(4-chloro-2,5-difluorophenyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((S)-(2-fluoro-4-(trifluoromethyl)phenyl)(1-hydroxycyclopropyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-((3-(((3R)-3-hydroxy-1-pyrrolidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-((3-(((3S)-3-hydroxy-1-pyrrolidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-(1H-imidazol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2,6-difluoro-3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(3-(diethylsulfamoyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-((7S)-bicyclo[4.2.0]octa-1,3,5-trien-7-yl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-fluoro-5-sulfamoylbenzoyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((5-(methylsulfonyl)-2-thiophenyl)carbonyl)-D-prolinamide;-   1-((3-(dimethylsulfamoyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((6-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   N—((S)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((6-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-cyano-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methylbenzyl)-D-prolinamide;-   (1R,2R,5S)-3-(3-(dimethylsulfamoyl)benzoyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((4-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-(2-chlorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)((3R)-1-methyl-5-oxo-3-pyrrolidinyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (3R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-(3-(methylsulfonyl)benzoyl)-3-morpholinecarboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(3-fluoro-3-oxetanyl)benzoyl)-D-prolinamide;-   (2R)—N—((R)-cyclopropyl(4-(difluoromethyl)-2-fluorophenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2-piperidinecarboxamide;-   N-((3R)-4-chloro-2,3-dihydro-1-benzofuran-3-yl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide    &    N-((3S)-4-chloro-2,3-dihydro-1-benzofuran-3-yl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-(4-pyridinyloxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (4S)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-hydroxy-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-(1H-pyrazol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-(2-chloro-3-methoxybenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(dimethylamino)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(3-fluoro-4-methoxyphenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(3-fluoro-4-methoxyphenyl)ethyl)-D-prolinamide;-   (5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-5-methyl-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((trans-3-cyanocyclobutyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (3R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((cis-4-(trifluoromethyl)cyclohexyl)methyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)-D-prolinamide;-   N-(3-chloro-4-methoxybenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D    prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-fluoro-3-methylphenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(4-fluoro-3-methylphenyl)ethyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((4-cyclopropyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(difluoromethoxy)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(4-(difluoromethoxy)phenyl)ethyl)-D-prolinamide;-   1-((3-(5-azaspiro[2.3]hex-5-ylsulfonyl)phenyl)carbonyl)-N-((1R)-1-(4-chlorophenyl)ethyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1-(((3S)-1-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (1S,3R,5S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(3-fluoro-3-oxetanyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((4-methyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N-((1S,2S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-hydroxypropyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-methoxy-5-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((2,6-dimethyl-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(3-(1-cyanocyclopropyl)benzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D    prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(difluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-3-methylbenzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-6-methylbenzyl)-D-prolinamide;-   (1R,3R,5R)-2-(3-benzoylbenzoyl)-N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azaspiro[3.3]heptane-1-carboxamide;-   (1S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azaspiro[3.3]heptane-1-carboxamide;-   N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)-2-((5-cyclopropyl-3-pyridinyl)carbonyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-methoxy-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-((6-chloro-3-pyridinyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-methoxy-2-methylbenzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((6-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-5-methyl-1-(3-(methylsulfonyl)benzoyl)-L-prolinamide;-   (1R,3R,5R)—N-(4-chloro-2,5-difluorobenzyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-(5-chloro-2-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (4R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (2R)—N-((6-chloro-3-pyridinyl)methyl)-1-((3-((cis-3-cyanocyclobutyl)sulfonyl)phenyl)carbonyl)-2-piperidinecarboxamide;-   (2R)—N-((6-chloro-3-pyridinyl)methyl)-1-((3-((trans-3-cyanocyclobutyl)sulfonyl)phenyl)carbonyl)-2-piperidinecarboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((2-methyl-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-5-fluoro-6-methoxy-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-5-fluoro-6-methoxy-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3,5,6-tetrafluorobenzyl)-D-prolinamide;-   (4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-methyl-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-methoxyphenyl)propyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(4-methoxyphenyl)propyl)-D-prolinamide;-   1-(((3S)-1-((trans-3-carbamoylcyclobutyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-2,2-dimethyl-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-((1S)-1-(4-chloro-3-fluorophenyl)propyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide;-   N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)propyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(difluoromethoxy)-3-methoxyphenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(4-(difluoromethoxy)-3-methoxyphenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(5-fluoro-2-methoxyphenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(5-fluoro-2-methoxyphenyl)ethyl)-D-prolinamide;-   N-((1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide;-   1-((3-(5-azaspiro[2.3]hex-5-ylsulfonyl)phenyl)carbonyl)-N-((1R)-1-(3,4-dichlorophenyl)ethyl)-D-prolinamide;-   N-((1R)-1-(4-chloro-2,5-difluorophenyl)ethyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-4-hydroxy-1-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   1-(((2R)-4-((3-cyano-1-azetidinyl)sulfonyl)-1-methyl-2-piperazinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-1-methyl-2-piperazinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-ethyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4R)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-4-hydroxy-1-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-5-methylbenzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-methylbenzyl)-D-prolinamide-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-D-prolinamide;-   1-(((3S)-1-((1,1-dioxido-3-thietanyl)sulfamoyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-methoxy-5-(methylsulfonyl)benzoyl)-2-piperidinecarboxamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((2-(2-methyl-2-propanyl)-   4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-pyrrolidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(3-(methoxy(methyl)sulfamoyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1S,3R,5S)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,5-dichlorobenzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-D-prolinamide;-   (2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((1,1-dioxido-2,3-dihydro-1-benzothiophen-6-yl)carbonyl)-2-piperidinecarboxamide;-   1-(((3S)-1-(1-oxa-6-azaspiro[3.3]hept-6-ylsulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((6-(trifluoromethyl)-2-pyridinyl)methyl)-D-prolinamide;-   (4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-(difluoromethyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((3R)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-D-prolinamide    &    1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((3S)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((4-methyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-6-(trifluoromethyl)benzyl)-D-prolinamide;-   N-(2-chloro-5-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((4-ethyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   N-(4-chloro-3-fluorobenzyl)-1-(((3S)-1-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-(3-oxetanylsulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-methyl-5-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((6-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   1-(((3S)-1-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (2S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methyl-1-(3-(methylsulfonyl)benzoyl)-2-azetidinecarboxamide;-   (3R)-2-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide;-   (3S)-2-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-methoxy-3-methylbenzyl)-D-prolinamide;-   N—((S)-(3-fluoro-3-oxetanyl)(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-5-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((S)-(3-fluoro-3-oxetanyl)(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (2R)-1-((3-(dimethylsulfamoyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-piperidinecarboxamide;-   (2S)-1-((3-(dimethylsulfamoyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-piperidinecarboxamide;-   1-(3-(dimethylsulfamoyl)benzoyl)-N-((1S)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-(1H-1,2,4-triazol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-5-methoxybenzyl)-D-prolinamide;-   (4R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-(difluoromethyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   (4S)-4-fluoro-1-(((3S)-1-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluorobenzyl)-D-prolinamide;-   (1R,3R,5R)—N—((S)-(2-fluoro-4-(trifluoromethyl)phenyl)((3S)-5-oxo-3-pyrrolidinyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(cyclopropylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(2-chloro-5-sulfamoylbenzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   1-(((3S)-1-((3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(4-fluoro-3-(methylsulfonyl)benzoyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(3-methyl-3-oxetanyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-((methoxyacetyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (4R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-methyl-3-(3-(methylsulfonyl)benzoyl)-2-oxo-4-imidazolidinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,5-difluorobenzyl)-L-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((5-methyl-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-methyl-3-(3-(methylsulfonyl)benzoyl)-2-oxo-4-imidazolidinecarboxamide;-   (4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-methyl-3-(3-(methylsulfonyl)benzoyl)-2-oxo-4-imidazolidinecarboxamide;-   1-(((3S)-1-(((2R)-2-(4-chlorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-(((2S)-2-(4-chlorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-(difluoromethoxy)-4-fluorophenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-(4-chlorobenzyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(5-fluoro-2-methoxybenzyl)-D-prolinamide;-   1-(3-cyanobenzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-methyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3,3-difluoro-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(1-(methylsulfonyl)-3-azetidinyl)benzoyl)-D-prolinamide;-   N-((7R)-bicyclo[4.2.0]octa-1,3,5-trien-7-yl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N-((7S)-bicyclo[4.2.0]octa-1,3,5-trien-7-yl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   (4S)-4-fluoro-N—((S)-(3-fluoro-3-oxetanyl)(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-(2-pyridinyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-ethoxy-3-fluorobenzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,6-dimethylbenzyl)-D-prolinamide;-   1-(((3S)-1-((3-((cyclopropylcarbonyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4R)-2-methyl-1,2,3,4-tetrahydro-4-isoquinolinyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4S)-2-methyl-1,2,3,4-tetrahydro-4-isoquinolinyl)-D-prolinamide;-   1-(((3S)-1-((3-(dimethylcarbamoyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-cyclopropyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methyl-5-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-methylbenzoyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-methyl-5-sulfamoylbenzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-methyl-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)-2-((4-cyclopropyl-2-pyridinyl)carbonyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-(2-chloro-6-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-(((2R)-2-benzyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-(((2S)-2-benzyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(4-(difluoromethyl)-2-fluorophenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   3-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-(((2-(trifluoromethyl)-4-pyridinyl)methyl)amino)ethyl)benzamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (3-oxetanyl)methyl)-4-hydroxy-1-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(((2S)-4-(methylsulfonyl)-2-piperazinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(3-thiophenyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)    (3-oxetanyl)methyl)-2-(4-methyl-3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(2,4-difluorophenyl)(3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-fluorophenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(4-fluorophenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1S,3R,5S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (2S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2-azetidinecarboxamide;-   N-((1R)-1-(4-chlorophenyl)-2-hydroxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-tert-butoxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-pentyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((2-methyl-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(1H-pyrazol-4-yl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2-fluorophenyl)(3-oxetanyl)methyl)-2-((2-(2-methyl-2-propanyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-((3R)-tetrahydro-3-furanyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-((3S)-tetrahydro-3-furanyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-2,2-dimethyl-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(5-methyl-2-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(3-(methylsulfonyl)benzoyl)-N-((1R)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;-   1-(((3S)-1-((6-hydroxy-6-(trifluoromethyl)-2-azaspiro[3.3]hept-2-yl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-(dimethylsulfamoyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(1H-pyrazol-3-yl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-methoxyphenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((2-(2-propanyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(3-(methyl(2-propyn-1-yl)sulfamoyl)benzoyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-(((6R)-6-hydroxy-2-azaspiro[3.4]oct-2-yl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-(((6S)-6-hydroxy-2-azaspiro[3.4]oct-2-yl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-1-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-(S-methylsulfonimidoyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N-((1R)-5-chloro-2,3-dihydro-1H-inden-1-yl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-((cyclobutylcarbonyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)-2-(2-aminobenzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (3R)—N—((R)-cyclopropyl(4-(trifluoromethyl)phenyl)methyl)-3-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N-((1S,2R)-1-(4-chloro-2,5-difluorophenyl)-2-hydroxypropyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N-benzyl-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(cis-3-(trifluoromethyl)cyclobutyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(trans-3-(trifluoromethyl)cyclobutyl)-D-prolinamide;-   1-(((3S)-1-((3-fluoro-3-(trifluoromethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-D-prolinamide;-   N—((S)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-D-prolinamide;-   (1S,3R,5S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2,3-difluorophenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(2,3-difluorophenyl)ethyl)-D-prolinamide;-   methyl    N-((3-(((2R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)-1-pyrrolidinyl)carbonyl)phenyl)sulfonyl)glycinate;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,5-dimethylbenzyl)-D-prolinamide;-   1-(((3S)-1-((3R)-tetrahydro-3-furanylsulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3S)-tetrahydro-3-furanylsulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (2R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-3,3-difluoro-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azetidinecarboxamide;-   (2S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-3,3-difluoro-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azetidinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;-   1-(((3S)-1-(((2R)-2-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-(((2S)-2-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-(5-chloro-2-methoxybenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N-(4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-(3-(trifluoromethyl)phenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   N-((1R)-1-(4-chloro-3-fluorophenyl)propyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(((3S)-1-((3,3-difluoro-1-pyrrolidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-(((5-methyl-1,3,4-oxadiazol-2-yl)methyl)sulfamoyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   methyl    trans-3-(((3S)-3-(((2R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)-1-pyrrolidinyl)carbonyl)-1-piperidinyl)sulfonyl)cyclobutanecarboxylate;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-2,2,2-trifluoro-1-(3-fluoro-4-methoxyphenyl)ethyl)-D-prolinamide;-   1-(2-chloro-4-fluoro-5-sulfamoylbenzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   3-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1S)-1-methyl-2-oxo-2-((4-(trifluoromethyl)benzyl)amino)ethyl)benzamide;-   (1S,3R,5S)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-(cyclobutylsulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-(difluoromethoxy)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-(acetylamino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4R)-6-methoxy-3,4-dihydro-2H-chromen-4-yl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-methoxybenzoyl)-D-prolinamide;-   1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-phenylethyl)-D-prolinamide;-   (1R,3R,5R)-2-((4-ethyl-2-pyridinyl)carbonyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-(2,2,2-trifluoroethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   1-(((3S)-1-((3-(methoxymethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((6-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(3,5-dichlorobenzyl)-D-prolinamide;-   (5S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-5-methyl-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (4S)—N—((R)-cyclopropyl(3-fluoro-4-methylphenyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   1-(3-(ethylsulfonyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(2-hydroxy-2-propanyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(3-(1-acetyl-3-fluoro-3-azetidinyl)benzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-methyl-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (2R)-1-((3-((3,3-difluoro-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-2-piperidinecarboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R,2R)-2-(trifluoromethyl)cyclobutyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R,2S)-2-(trifluoromethyl)cyclobutyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S,2R)-2-(trifluoromethyl)cyclobutyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S,2S)-2-(trifluoromethyl)cyclobutyl)-D-prolinamide;-   1-(((3S)-1-(1-azaspiro[3.3]hept-1-ylsulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   (1R,3S,5R)-2-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((S)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide;-   N-((1S)-1-(4-chlorophenyl)ethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-methoxyphenyl)propyl)-D-prolinamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(2-methoxyphenyl)propyl)-D-prolinamide;-   1-(4-amino-3-(methylsulfonyl)benzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   1-(((3S)-1-((1-acetyl-3-azetidinyl)sulfamoyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;-   N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)-2-(2-methoxy-5-(methylsulfonyl)benzoyl)-N—((R)-3-oxetanyl(4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   N—((S)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(3-fluoro-4-methylphenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((S)-(4-chloro-2,5-difluorophenyl)(3-fluorooxetan-3-yl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)-2-(2-amino-5-(methylsulfonyl)benzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-(hydroxymethyl)-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(2-methoxyisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(5-methylthiophene-2-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((S)-1-(4-chloro-2,5-difluorophenyl)-2,2-difluoroethyl)-2-(5-(methylsulfonyl)nicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(1,4-dimethyl-1H-pyrazole-5-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3-(2-hydroxypropan-2-yl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(5-methyl-1H-indazole-7-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)-2-(5-chloro-1H-indazole-7-carbonyl)-N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(5-(1-hydroxyethyl)-2-methylisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(5-(trifluoromethyl)isoxazole-3-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3,4-dimethylisoxazole-5-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3,5-dimethylisoxazole-4-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3-(trifluoromethyl)isoxazole-5-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)    ((1s,3S)-3-hydroxycyclobutyl)methyl)-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide;-   (R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)    ((1r,3R)-3-hydroxycyclobutyl)methyl)-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide;-   (1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)((1r,3R)-3-hydroxy-3-methylcyclobutyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)((1 s,    3S)-3-hydroxycyclobutyl)methyl)-2-(2-(difluoromethyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)((1r,3R)-3-hydroxycyclobutyl)methyl)-2-(2-(difluoromethyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((S)-(2,5-difluoro-4-(trifluoromethyl)phenyl)((R)-5-oxopyrrolidin-3-yl)methyl)-2-(2-(trifluoromethyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethoxy)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;    and-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide    or a pharmaceutically acceptable salt thereof.

In a Nineteenth Embodiment, the Invention Provides a Compound as Recitedin Table B, or a Pharmaceutically Acceptable Salt Thereof:

TABLE B

-   (1R,3R,5R)-2-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-(ethylamino)-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-(cyclopropylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(trifluoromethyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)-2-(3-(ethylsulfonyl)benzoyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-sulfamoylbenzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclobutyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(cyclopropylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)    (3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(cyclopropylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-4-fluoro-1-((6-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,5-difluorobenzyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((S)-(4-chloro-2,5-difluorophenyl)(1-hydroxycyclopropyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4,4-difluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,2R,5S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-3-(3-sulfamoylbenzoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2-fluorophenyl)(cyclopropyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   (R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide;-   (2R,4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)    pyrrolidine-2-carboxamide;-   (1R,3R,5R)—N-((1S,2S)-1-(4-chloro-2,5-difluorophenyl)-2-hydroxypropyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,2R,5S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-(3-(methylsulfonyl)benzoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   (4S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-4-fluoro-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;-   (1R,2R,5S)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-3-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;    and-   (1S,3R,5S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide,    or a pharmaceutically acceptable salt thereof.

In a Twentieth Embodiment, the Invention Provides a Compound as Recitedin Table C, or a Pharmaceutically Acceptable Salt Thereof:

TABLE C

-   N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(cyclopropylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;-   (R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)    pyrrolidine-2-carboxamide;-   (2R,4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide;-   (4S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide;    and-   (4S)—N—((R)-(4-chloro-2,5-difluorophenyl)    (cyclopropyl)methyl)-4-fluoro-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide,    or a pharmaceutically acceptable salt thereof.

In further embodiments, provided herein are compounds as disclosedherein in the form of a pharmaceutically acceptable salt.

In a further embodiment, the invention provides methods of makingcompounds of formula I or a subformulae thereof.

The method comprising the synthetic steps of:

(a) Coupling protected amino acid,

with carboxylic acid, Q-CO₂H, under conditions conducive to amide bondformation to generate intermediate:

wherein PG represents a carboxylic acid protecting group stable to theamide coupling reaction conditions;

(b) Removing protecting group, PG, to generate free acid:

(c) Coupling the carboxylic acid generated in step (b) with a primaryamine,

under conditions conducive to amide bond formation to generate thecompound of formula (I), wherein variables Q, X¹, X², X³, X⁴, X⁵, R¹,R^(1a), R¹³, R^(13a) and R¹⁴ have the definitions provided in the firstembodiment.

In a further embodiment, the invention provides methods of makingcompounds of formula I or a subformulae thereof.

The method comprising the synthetic steps of:

(a) Coupling protected amino acid,

with primary amine

under conditions conducive to amide bond formation to generateintermediate:

wherein PG represents an amide protecting group stable to the amidecoupling reaction conditions;

(b) Removing protecting group, PG, to generate free amine

(c) Coupling the amine generated in step (b) with a carboxylic acid,Q-CO₂H under conditions conducive to amide bond formation to generatethe compound of formula (I), wherein variables Q, X¹, X², X³, X⁴, X⁵,R¹, R^(1a), R¹³, R^(13a) and R¹⁴ have the definitions provided in thefirst embodiment.

In a further embodiment, the invention provides other methods of makingcompounds of the fifteenth embodiment, e.g., compounds of formula II ora subformulae thereof.

The method comprising the synthetic steps of:

(a) Coupling protected amino acid,

with carboxylic acid,

under conditions conducive to amide bond formation to generateintermediate:

wherein PG represents a carboxylic acid protecting group stable to theamide coupling reaction conditions;

(b) Removing protecting group, PG, to generate free acid:

(c) Coupling the carboxylic acid generated in step (b) with a primaryamine,

under conditions conducive to amide bond formation to generate thecompound of Formula (II), wherein variables W, X⁴, Z², Z³, R¹, R²,R^(3a), R⁸, R^(15a), R^(15b) and R¹⁶ have the definitions provided inthe fifteenth embodiment.

In a further embodiment, the invention provides methods of makingcompounds of formula II or a subformulae thereof.

The method comprising the synthetic steps of:

(a) Coupling protected amino acid,

with primary amine

under conditions conducive to amide bond formation to generateintermediate:

wherein PG represents an amide protecting group stable to the amidecoupling reaction conditions;

(b) Removing protecting group, PG, to generate free amine:

(c) Coupling the amine generated in step (b) with a carboxylic acid,

under conditions conducive to amide bond formation to generate thecompound of formula (I), wherein variables W, X⁴, Z², Z³, R¹, R²,R^(3a), R⁸, R^(15a), R^(15b) and R¹⁶ have the definitions provided inthe fifteenth embodiment.

In a further embodiment, the invention provides other methods of makingcompounds of the fifteenth embodiment, e.g., compounds of formula IIa.

the method comprising the synthetic steps of:

(a) Coupling protected amino acid,

with carboxylic acid,

under conditions conducive to amide bond formation to generateintermediate:

wherein PG represents a carboxylic acid protecting group stable to theamide coupling reaction conditions;

(b) Removing protecting group, PG, to generate free acid:

(c) Coupling the carboxylic acid generated in step (b) with a primaryamine,

under conditions conducive to amide bond formation to generate thecompound of Formula (IIa), wherein variables X⁴, Z², Z³, R¹, R², R^(3a),R⁸, R^(15a), R^(15b) and R¹⁶ have the definitions provided in thefifteenth embodiment.

In a further embodiment, the invention provides other methods of makingcompounds of the fifteenth embodiment, e.g., compounds of formula IIa.

The method comprising the synthetic steps of:

(a) Coupling protected amino acid,

with amine,

under conditions conducive to amide bond formation to generateintermediate:

wherein PG represents a carboxylic acid protecting group stable to theamide coupling reaction conditions;

(b) Removing protecting group, PG, to generate free acid:

(c) Coupling the carboxylic acid generated in step (b) with a primaryamine,

under conditions conducive to amide bond formation to generate thecompound of Formula (IIa), wherein variables X⁴, Z², Z³, R¹, R², R^(3a),R⁸, R^(15a), R^(15b) and R¹⁶ have the definitions provided in thefifteenth embodiment.

In a further embodiment, the invention provides other methods of makingcompounds of the fifteenth embodiment, e.g., compounds of formula IIb.

The method comprising the synthetic steps of:

(a) Coupling protected amino acid,

with carboxylic acid,

under conditions conducive to amide bond formation to generateintermediate:

wherein PG represents a carboxylic acid protecting group stable to theamide coupling reaction conditions;

(b) Removing protecting group, PG, to generate free acid:

(c) Coupling the carboxylic acid generated in step (b) with a primaryamine,

under conditions conducive to amide bond formation to generate thecompound of Formula (IIb), wherein X⁴, Z², Z³, R¹, R², R^(3a) and R⁸have the definitions provided in the fifteenth embodiment.

In a further embodiment, the invention provides other methods of makingcompounds of the fifteenth embodiment, e.g., compounds of formula IIb.

The method comprising the synthetic steps of:

(a) Coupling protected amino acid,

with primary amine

under conditions conducive to amide bond formation to generateintermediate:

wherein PG represents an amide protecting group stable to the amidecoupling reaction conditions;

(b) Removing protecting group, PG, to generate free amine:

(c) Coupling the amine generated in step (b) with a carboxylic acid,

under conditions conducive to amide bond formation to generate thecompound of formula (IIb), wherein variables X⁴, Z², Z³, R¹, R², R^(3a)and R⁸ have the definitions provided in the fifteenth embodiment.

In a further embodiment, the invention provides other methods of makingcompounds of the seventeenth embodiment, e.g., compounds of formula IIIor a subformulae thereof.

The method comprising the synthetic steps of:

(a) Coupling protected amino acid,

with carboxylic acid,

under conditions conducive to amide bond formation to generateintermediate:

wherein PG represents a carboxylic acid protecting group stable to theamide coupling reaction conditions;

(b) Removing protecting group, PG, to generate free acid:

(c) Coupling the carboxylic acid generated in step (b) with a primaryamine,

under conditions conducive to amide bond formation to generate thecompound of Formula (III), wherein variables A, W, X⁴, R¹, R², R^(3a),R⁸, R⁹, R¹⁰, R¹², R^(15a), R^(15b) and R¹⁶ have the definitions providedin the seventeenth embodiment. In certain compounds of formula (III),when A is NH, the amine may be optionally masked with a suitableprotecting group during transformations (a), (b) and/or (c).

In a further embodiment, the invention provides methods of makingcompounds of formula III or a subformulae thereof.

The method comprising the synthetic steps of:

(a) Coupling protected amino acid,

with primary amine

under conditions conducive to amide bond formation to generateintermediate:

wherein PG represents an amide protecting group stable to the amidecoupling reaction conditions;

(b) Removing protecting group, PG, to generate free amine:

(c) Coupling the amine generated in step (b) with a carboxylic acid,

under conditions conducive to amide bond formation to generate thecompound of Formula (III), wherein variables A, W, X⁴, R¹, R², R^(3a),R⁸, R⁹, R¹⁰, R¹², R^(15a), R^(15b) and R¹⁶ have the definitions providedin the seventeenth embodiment. In certain compounds of formula (III),when A is NH, the amine may be optionally masked with a suitableprotecting group during transformation (c).

In a further embodiment, the invention provides other methods of makingcompounds of the seventeenth embodiment, e.g., compounds of formulaIIIa:

The method comprising the synthetic steps of:

(a) Coupling protected amino acid,

with carboxylic acid,

under conditions conducive to amide bond formation to generateintermediate:

wherein PG represents a carboxylic acid protecting group stable to theamide coupling reaction conditions;

(b) Removing protecting group, PG, to generate free acid:

(c) Coupling the carboxylic acid generated in step (b) with a primaryamine,

under conditions conducive to amide bond formation to generate thecompound of Formula (III), wherein variables A, W, X⁴, R¹, R², R^(3a),R⁹, R¹⁰, R¹², R^(15a), R^(15b) and R¹⁶ have the definitions provided inthe seventeenth embodiment. In certain compounds of formula (III), whenA is NH, the amine may be optionally masked with a suitable protectinggroup during transformations (a), (b) and/or (c).

In a further embodiment, the invention provides methods of makingcompounds of formula IIIa or a subformulae thereof.

The method comprising the synthetic steps of:

(a) Coupling protected amino acid,

with primary amine

under conditions conducive to amide bond formation to generateintermediate:

wherein PG represents an amide protecting group stable to the amidecoupling reaction conditions;

(b) Removing protecting group, PG, to generate free amine:

(c) Coupling the amine generated in step (b) with a carboxylic acid,

under conditions conducive to amide bond formation to generate thecompound of Formula (III), wherein variables A, W, X⁴, R¹, R², R^(3a),R⁸, R⁹, R¹⁰, R¹², R^(15a), R^(15b) and R¹⁶ have the definitions providedin the seventeenth embodiment. In certain compounds of formula (III),when A is NH, the amine may be optionally masked with a suitableprotecting group during transformation (c).

In another embodiment, pharmaceutical compositions are provided whichcomprise one or more pharmaceutically acceptable carriers and atherapeutically effective amount of a compound of any one of formulae Ior a subformulae thereof. In some aspects, the composition is formulatedin a form selected from the group consisting of an injectable fluid, anaerosol, a tablet, a pill, a capsule, a syrup, a cream, a gel and atransdermal patch.

In another embodiment, combinations, in particular pharmaceuticalcombinations, are provided which comprise a therapeutically effectiveamount of the compound any one of formulae I or a subformulae thereof.

In another embodiment, methods of modulating cardiac sarcomere activityin a subject are provided which methods comprise administering to thesubject a therapeutically effective amount of Formula I or a subformulaethereof. In preferred aspects of the embodiment, methods of activatingcardiac sarcomere activity in a subject are provided, which methodscomprise administering to the subject a therapeutically effective amountof a compound of Formula I or subformulae thereof.

In yet other embodiments, methods of treating a disorder or a disease ina subject mediated by cardiac sarcomere activity, in particular methodsof treating a disease or disorder in which activation of the cardiacsarcomere would be beneficial, are provided. The methods compriseadministering to the subject a therapeutically effective amount of thecompound of Formula I or a subformulae thereof.

In another embodiment, methods of treating heart failure, or morepreferably systolic heart failure, in a subject are provided whichmethods comprise administering to the subject a therapeuticallyeffective amount of the compound of Formula I or a subformulae thereof.In certain aspects, the invention provides methods of treating systolicheart failure which method comprises the step of administering to asubject in need of therapy a therapeutically effective amount of acompound or salt of Formula I or a subformulae thereof.

In another aspect, the invention provides for the use of compounds ofFormula I or a subformulae thereof for use in the preparation of amedicament and more particularly for use in the manufacture of amedicament for the treatment of a disorder or disease in a subjectmediated by cardiac sarcomere activity. In certain other aspects, theinvention provides for the use of a compound according of any one offormulae I or a subformulae thereof in the treatment of heart failureand more preferably in the treatment of systolic heart failure. Incertain aspects, the invention provides the use of a compound accordingof any one of formulae I or a subformulae thereof in the treatment ofsystolic dysfunction.

In one embodiment, the invention provides a combination, in particular apharmaceutical combination, comprising a therapeutically effectiveamount of the compound according to the definition of formula I orsubformulae thereof or any one of the specifically disclosed compoundsof the invention and one or more therapeutically active agents(preferably selected from those listed infra).

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety having up to 20 carbon atoms. Unlessotherwise provided, alkyl refers to hydrocarbon moieties having 1 to 20carbon atoms, 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbonatoms, or 1 to 4 carbon atoms. Representative examples of alkyl include,but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl,n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

As used herein, the term “alkylene” refers to divalent alkyl group asdefined herein above having 1 to 20 carbon atoms. Unless otherwiseprovided, alkylene refers to moieties having 1 to 20 carbon atoms, 1 to16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4carbon atoms. Representative examples of alkylene include, but are notlimited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene,sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene,neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene,2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, n-decyleneand the like.

As used herein, the term “haloalkyl” refers to an alkyl as definedherein, which is substituted with one or more halo groups as definedherein. The haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkylincluding perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloroor fluoro within the alkyl group. Dihaloalky and polyhaloalkyl groupscan have two or more of the same halo atoms or a combination ofdifferent halo groups within the alkyl. Typically the polyhaloalkylcontains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups.Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. A perhaloalkyl refers to an alkyl having all hydrogenatoms replaced with halo atoms. It is understood that haloalkyl can beused to describe haloalkyl groups having a particular number of carbonatoms. For example, a haloalkyl group containing 1 to 6 carbon atoms maybe referred to as “haloC₁-C₆alkyl.”

As used herein, the term “hydroxy alkyl” refers to an alkyl as definedherein which is substituted with one or more hydroxy groups. The term“hydroxy cycloalkyl-alkyl” refers to an alkyl group that is substitutedwith a cycloalkyl group, as defined herein, and further substituted witha hydroxy group. The hydroxy group can be on the alkyl group, thecycloalkyl group, or on each of the alkyl and cycloalkyl groups.

The term “aryl” refers to an aromatic hydrocarbon group having 6-20carbon atoms in the ring portion. Typically, aryl is monocyclic,bicyclic or tricyclic aryl having 6-20 carbon atoms. Furthermore, theterm “aryl” as used herein, refers to an aromatic substituent which canbe a single aromatic ring, or multiple aromatic rings that are fusedtogether. Non-limiting examples include phenyl, naphthyl ortetrahydronaphthyl, each of which may optionally be substituted with 1-4substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen,hydroxy, alkoxy, acyl, alkyl-C(O)—O—, aryl-O—, heteroaryl-O—, amino,thiol, alkyl-S—, aryl-S— nitro, cyano, carboxy, alkyl-O—C(O)—,carbamoyl, alkyl-S(O)—, sulfonyl, sulfonamido, phenyl, and heterocyclyl.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. Typically, alkoxy groups have about 1-7, more preferably about1-4 carbons.

As used herein, the term “heterocycle,” “heterocycloalkyl” or“heterocyclo” refers to a saturated or unsaturated non-aromatic ring orring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-,8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or15-membered tricyclic ring system and contains at least one heteroatomselected from O, S and N, where the N and S can also optionally beoxidized to various oxidation states. The heterocyclic group can beattached at a heteroatom or a carbon atom. The heterocyclyl can includefused or bridged rings as well as spirocyclic rings. Examples ofheterocycles include tetrahydrofuran, dihydrofuran, 1,4-dioxane,morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane,imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran,dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane,oxathiane, thiomorpholine, azetidine, thiazolidine, morpholine, and thelike.

As used herein, the term “cycloalkyl” refers to saturated or unsaturatedmonocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbonatoms. Unless otherwise provided, cycloalkyl refers to cyclichydrocarbon groups having between 3 and 9 ring carbon atoms or between 3and 7 ring carbon atoms, each of which can be optionally substitutedwith one, or two, or three, or more substituents independently selectedfrom the group consisting of alkyl, halo, oxo, hydroxy, alkoxy,alkyl-C(O)—, acylamino, carbamoyl, alkyl-NH—, (alkyl)₂N—, thiol,alkyl-S—, nitro, cyano, carboxy, alkyl-O—C(O)—, sulfonyl, sulfonamido,sulfamoyl, and heterocyclyl. Exemplary monocyclic hydrocarbon groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl and cyclohexenyl and the like. Exemplarybicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl,tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groupsinclude adamantyl and the like. The term “hydroxy cycloalkyl” refersspecifically to a cycloalkyl group substituted with one or more hydroxygroups.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to8 heteroatoms selected from N, O and S. In certain preferred aspects,the heteroaryl is a 5-10 membered ring system (e.g., 5-7 memberedmonocycle or an 8-10 membered bicycle) or a 5-7 membered ring system.Exemplary monocyclic heteroaryl groups include 2- or 3-thienyl, 2- or3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-,or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, and5-pyrimidinyl. Exemplary bicyclic heteroaryl groups include 1-, 3-, 4-,5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 1-, 2-, 4-, 5-, 6-, 7-, or8-benzimidazolyl and 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-indolyl.

The term “heteroaryl” also refers to a group in which a heteroaromaticring is fused to one or more aryl, cycloaliphatic, or heterocyclylrings, where the radical or point of attachment is on the heteroaromaticring

As used herein, the term “halogen” or “halo” refers to fluoro, chloro,bromo, and iodo.

As used herein, the term “optionally substituted” unless otherwisespecified refers to a group that is unsubstituted or is substituted withone or more, typically 1, 2, 3 or 4, suitable non-hydrogen substituents.If the identity of the “optional substituent” is not clearly defined incontext of the optionally substituted group, then each optionalsubstituent is independently selected from the group consisting of:alkyl, hydroxy, halogen, oxo, amino, alkylamino, dialkylamino, alkoxy,cycloalkyl, CO₂H, heterocycloalkyloxy (which denotes a heterocyclicgroup bonded through an oxygen bridge), —CO₂alkyl, mercapto, nitro,cyano, sulfamoyl, sulfonamide, aryl, —OC(O)alkyl, —OC(O)aryl, aryl-S—,aryloxy; alkylthio, formyl (i.e., HC(O)—), —C(O)NH₂, aralkyl (alkylsubstituted with aryl), aryl and aryl substituted with alkyl,cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(O)—NH—, alkylamino,dialkylamino or halogen. It is understood that where a group isindicated to be optionally substituted, the disclosure includesembodiments in which the group is unsubstituted as well as embodimentsin which the group is substituted.

The point of attachment of a given moiety to the parent structure can bereadily determined by one of skill in art. Thus, although the point ofattachment may not be explicitly shown, it would be evident to theskilled artisan based on common general knowledge in the chemical arts.For example, N(H)C(O)C₃-C₇cycloalkyl would be understood to be attachedto the parent structure at the available valency on the nitrogen atom.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. The use of “rel”indicates that the diastereomeric orientation is known but the absolutestereochemistry is not. In cases where the absolute stereochemistry hasnot been determined the optical rotation and/or chiral chromatographyconditions will indicate which isomer is present.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R—Ssystem. When a compound is a pure enantiomer the stereochemistry at eachchiral carbon may be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) which they rotateplane polarized light at the wavelength of the sodium D line orretention time on chiral chromatography separation. Certain of thecompounds described herein contain one or more asymmetric centers oraxes and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or with the (+) or (−) sign. Thepresent invention is meant to include all such possible isomers,including racemic mixtures, optically pure forms and intermediatemixtures. Optically active (R)- and (S)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. If the compound contains a double bond, the substituent maybe E or Z configuration. If the compound contains a disubstitutedcycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration.

It is understood that for any compound provided herein, including anycompound of Formula (I), or any embodiment thereof, or any compound ofTable A, B, or C, or a salt of any of the foregoing, the compound mayexist in any stereochemical form, such as a single enantiomer,diastereomer, or tautomer or a mixture of one or more enantiomers,diastereomers, and tautomers in any ratio.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutical acceptable salts”. The term “pharmaceuticallyacceptable salts” refers to salts that retain the biologicaleffectiveness and properties of the compounds of this invention and,which typically are not biologically or otherwise undesirable. In manycases, the compounds of the present invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,benzenesuflonic acid, toluenesulfonic acid, sulfosalicylic acid, and thelike.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper. In certainother embodiments, the salts are selected from ammonium, potassium,sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

In another aspect, the present invention provides compounds as disclosedherein in acetate, ascorbate, adipate, aspartate, benzoate, besylate,bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate,camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate,citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate,glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide,isethionate, lactate, lactobionate, laurylsulfate, malate, maleate,malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate,napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate,palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,polygalacturonate, propionate, sebacate, stearate, succinate,sulfosalicylate, sulfate, tartrate, tosylate trifenatate,trifluoroacetate or xinafoate salt form. In yet another aspect, thepresent invention provides compounds as disclosed herein in C₁-C₄alkylsufonic acid, benzenesulfonic acid or mono-, di- or tri-C₁-C₄alkylsubstituted benzene sufonic acid addition salt form.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁴I, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H, ¹³C, and ¹⁴O, are present. Such isotopicallylabelled compounds are useful in metabolic studies (with ¹⁴O), reactionkinetic studies (with, for example ²H or ³H), detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically labeled compounds of this inventionand salts thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has at least 50%deuterium incorporation at each designated deuterium atom, 60% deuteriumincorporation, at least 75% deuterium incorporation, at least 90%deuterium incorporation, at least 95% deuterium incorporation, at least99% deuterium incorporation, or at least 99.5% deuterium incorporation.

The compounds of the present invention may inherently or by design formsolvates with solvents (including water). Therefore, it is intended thatthe invention embrace both solvated and unsolvated forms. The term“solvate” refers to a molecular complex of a compound of the presentinvention (including salts thereof) with one or more solvent molecules.Such solvent molecules are those commonly used in the pharmaceuticalart, which are known to be innocuous to a recipient, e.g., water,ethanol, dimethylsulfoxide, acetone and other common organic solvents.The term “hydrate” refers to a molecular complex comprising a compoundof the invention and water. Pharmaceutically acceptable solvates inaccordance with the invention include those wherein the solvent ofcrystallization may be isotopically substituted, e.g. D₂O, d₆-acetone,d₆-DMSO.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder,or a disease or biological process (i) mediated by cardiac sarcomereactivity, or (ii) associated with cardiac sarcomere activity; or (2)increasing the activity of cardiac sarcomere. In another non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a cell, or a tissue, or a non-cellular biological material, or amedium, is effective to at least partially increase cardiac sarcomereactivity.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In certain embodiments, the subject is aprimate. In yet other embodiments, the subject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both.

As used herein, the term “prevent,” “preventing” or “prevention” of anydisease or disorder refers in one embodiment, to delay or avoidance ofonset of the disease or disorder (i.e., slowing or preventing the onsetof the disease or disorder in a patient susceptible to development ofthe disease or disorder).

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturatedbonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high performance liquidchromatography (HPLC) or supercritical fluid chromatography (SFC) usinga chiral adsorbent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known to those skilled in the art into theindividual isomers; diastereoisomers can be separated, for example, bypartitioning between polyphasic solvent mixtures, recrystallizationand/or chromatographic separation, for example over silica gel or bye.g. medium pressure liquid chromatography over a reversed phase column,and racemates can be separated, for example, by the formation of saltswith optically pure salt-forming reagents and separation of the mixtureof diastereoisomers so obtainable, for example by means of fractionalcrystallization, or by chromatography over optically active columnmaterials.

Within the scope of this text, a readily removable group that is not aconstituent of the particular desired end product of the compounds ofthe present invention is designated a “protecting group”, unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such asJ. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press,London and New York 1973, in T. W. Greene and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, Third edition, Wiley, New York 1999, in“The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), AcademicPress, London and New York 1981, in “Methoden der organischen Chemie”(Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/I,Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit,“Aminosauren, Peptide, Proteine” (Amino acids, Peptides, Proteins),Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in JochenLehmann, “Chemie der Kohlenhydrate: Monosaccharide and Derivate”(Chemistry of Carbohydrates: Monosaccharides and Derivatives), GeorgThieme Verlag, Stuttgart 1974. A characteristic of protecting groups isthat they can be removed readily (i.e. without the occurrence ofundesired secondary reactions) for example by solvolysis, reduction,photolysis or alternatively under physiological conditions (e.g. byenzymatic cleavage).

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g. using chromatographic methods,distribution methods, (re-) crystallization, and the like.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any process steps disclosed herein can be carried out under reactionconditions that are known to those skilled in the art, including thosementioned specifically, in the absence or, customarily, in the presenceof solvents or diluents, including, for example, solvents or diluentsthat are inert towards the reagents used and dissolve them, in theabsence or presence of catalysts, condensation or neutralizing agents,for example ion exchangers, such as cation exchangers, e.g. in theH+form, depending on the nature of the reaction and/or of the reactantsat reduced, normal or elevated temperature, for example in a temperaturerange of from about −100° C. to about 250° C., including, for example,from approximately −80° C. to approximately 250° C., for example at from−80 to −60° C., at room temperature, at from −20 to 40° C. or at refluxtemperature, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder an argon or nitrogen atmosphere.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane,liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, suchas methanol, ethanol or 1- or 2-propanol, nitriles, such asacetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, methycyclohexane, or mixtures of those solvents, for exampleaqueous solutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In a further embodiment, the composition comprisesat least two pharmaceutically acceptable carriers, such as thosedescribed herein. For purposes of the present invention, unlessdesignated otherwise, solvates and hydrates are generally consideredcompositions. Preferably, pharmaceutically acceptable carriers aresterile. The pharmaceutical composition can be formulated for particularroutes of administration such as oral administration, parenteraladministration, and rectal administration, etc. In addition, thepharmaceutical compositions of the present invention can be made up in asolid form (including without limitation capsules, tablets, pills,granules, powders or suppositories), or in a liquid form (includingwithout limitation solutions, suspensions or emulsions). Thepharmaceutical compositions can be subjected to conventionalpharmaceutical operations such as sterilization and/or can containconventional inert diluents, lubricating agents, or buffering agents, aswell as adjuvants, such as preservatives, stabilizers, wetting agents,emulsifiers and buffers, etc.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, and the like and combinations thereof, as would be known to thoseskilled in the art (see, for example, Remington® PharmaceuticalSciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Exceptinsofar as any conventional carrier is incompatible with the activeingredient, its use in the therapeutic or pharmaceutical compositions iscontemplated.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with one or more of:a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearicacid, its magnesium or calcium salt and/or polyethyleneglycol; fortablets also c) binders, e.g., magnesium aluminum silicate, starchpaste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and/or polyvinylpyrrolidone; if desired d)disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and e) absorbents, colorants, flavors andsweeteners. Tablets may be either film coated or enteric coatedaccording to methods known in the art. Suitable compositions for oraladministration include an effective amount of a compound of theinvention in the form of tablets, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsion, hard or soft capsules, orsyrups or elixirs. Compositions intended for oral use are preparedaccording to any method known in the art for the manufacture ofpharmaceutical compositions and such compositions can contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tablets maycontain the active ingredient in admixture with nontoxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil. Certain injectablecompositions are aqueous isotonic solutions or suspensions, andsuppositories are advantageously prepared from fatty emulsions orsuspensions. Said compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Said compositions are prepared according toconventional mixing, granulating or coating methods, respectively, andcontain about 0.1-75%, or contain about 1-50%, of the active ingredient.Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives. Asused herein a topical application may also pertain to an inhalation orto an intranasal application. They may be conveniently delivered in theform of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurized container, pump, spray, atomizer ornebulizer, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

Prophylactic and Therapeutic Uses

The compounds disclosed herein in free form or in pharmaceuticallyacceptable salt form, exhibit valuable pharmacological properties, e.g.cardiac sarcomere modulating properties and more particularly cardiacsarcomere activating properties e.g. as indicated in in vitro and invivo tests as provided in the next sections and are therefore indicatedfor therapy.

The present invention provides methods of treating a disease or disorderassociated with heart muscle contractility by administering to a subjectin need thereof an effective amount of a compound disclosed herein. Incertain aspects, methods are provided for the treatment of diseasesassociated with increasing activity of the cardiac sarcomere.

In a specific embodiment, the present invention provides a method oftreating or preventing heart failure by administering to a subject inneed thereof an effective amount of a compound disclosed herein. Incertain embodiments, patients who are currently asymptomatic but are atrisk of developing heart failure are suitable for administration with acompound of the invention. The methods of treating or preventing heartfailure include, but are not limited to, methods of treating orpreventing systolic heart failure.

In some embodiments, the present invention provides methods of treatinga disease or disorder associated with decreased ejection fraction fromthe heart, e.g., heart failure by administering to a subject in needthereof an effective amount of a compound disclosed herein. Examples ofknown heart failure patient populations associated with reduced orcompromised ejection fraction include systolic heart failure.

In some embodiments, the compounds disclosed herein are used in thetreatment or prevention of heart failure with reduced ejection fraction(HFrEF) or systolic heart failure, dilated cardiomyopathy, postpartumcardiomyopathy, idiopathic cardiomyopathy, pediatric HFrEF,chemotherapy-induced heart failure, heart failure associated withmuscular dystrophy, bi-ventricular HFrEF, HFrEF with pulmonaryhypertension, heart failure with preserved ejection fraction (HFpEF)with right ventricular dysfunction, pulmonary hypertension with rightventricular dysfunction, scleroderma with pulmonary hypertension, rightventricular dysfunction, Chagas disease, or myocarditis. In someembodiments, provided herein are methods of treating or preventing heartfailure with reduced ejection fraction or systolic heart failure,dilated cardiomyopathy, postpartum cardiomyopathy, idiopathiccardiomyopathy, pediatric HFrEF, chemotherapy-induced heart failure,heart failure associated with muscular dystrophy, bi-ventricular HFrEF,HFrEF with pulmonary hypertension, heart failure with preserved ejectionfraction (HFpEF) with right ventricular dysfunction, pulmonaryhypertension with right ventricular dysfunction, scleroderma withpulmonary hypertension, right ventricular dysfunction, Chagas disease,or myocarditis, which methods comprise administering to a subject inneed thereof an effective amount of one or more compounds disclosedherein. Also provided herein is the use of one or more compoundsdisclosed herein in the manufacture of a medicament for the treatment orprevention of heart failure with reduced ejection fraction or systolicheart failure, dilated cardiomyopathy, postpartum cardiomyopathy,idiopathic cardiomyopathy, pediatric HFrEF, chemotherapy-induced heartfailure, heart failure associated with muscular dystrophy,bi-ventricular HFrEF, HFrEF with pulmonary hypertension, heart failurewith preserved ejection fraction (HFpEF) with right ventriculardysfunction, pulmonary hypertension with right ventricular dysfunction,scleroderma with pulmonary hypertension, right ventricular dysfunction,Chagas disease, or myocarditis.

In some embodiments, the dilated cardiomyopathy is selected from thegroup consisting of genetic dilated cardiomyopathy, peripartumcardiomyopathy (e.g., post-partum cardiomyopathy), idiopathic dilatedcardiomyopathy, post-infectious dilated cardiomyopathy, toxin-induceddilated cardiomyopathy, and nutritional deficiency dilatedcardiomyopathy. In some embodiments, the pediatric HFrEF occurs inpediatric patients with univentricular hearts or a single ventricle orpatients post Fontan or Fontan-Kreutzer procedure. In some embodiments,the pediatric HFrEF is pediatric heart failure associated withcongenital heart disease. In some embodiments, the chemotherapy-inducedheart failure is selected from the group consisting ofchemotherapy-induced left ventricular dysfunction, radiation-inducedheart failure, heart failure resulting from anthracycline treatment(including but not limited to doxorubicin, epirubicin, anddaunorubicin), heart failure resulting from antiERBB2 treatment(including but not limited to trastuzumab and lapatinib), heart failureresulting from VEGF inhibitor treatment (including but not limited tobevacizumab), and heart failure resulting from tyrosine-kinase inhibitortreatment (including but not limited to imatinib, dasatinib, nilotinim,sorafenib, and sunitinib). In some embodiments, the heart failureassociated with muscular dystrophy is selected from the group consistingof heart failure associated with Duchenne muscular dystrophy, heartfailure associated with Becker muscular dystrophy, heart failureassociated with myotonic dystrophy (e.g., Steinert's disease), heartfailure associated with laminopathies such as Emery-Dreifuss musculardystrophy (EDMD), including both X-linked EDMD and autosomal dominantEDMD, heart failure associated with facioscapulohumeral musculardystrophy (FSHMD), heart failure associated with Limb-girdle musculardystrophy, including sarcoglycanopathies and the autosomal dominant formof the disease, and heart failure associated with congenital musculardystrophy. In some embodiments, the pulmonary hypertension with rightventricular dysfunction is associated with high left ventricular(diastolic) pressure in HFrEF or high left ventricular (diastolic)pressure in HFpEF.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

The activity of a compound according to the present invention can beassessed by in vitro & in vivo methods, such as those described in theexamples below.

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents.

In one embodiment, the invention provides a product comprising acompound disclosed herein and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease orcondition mediated by the cardiac sarcomere. In preferred aspects, thetherapy is a treatment for heart failure having reduced or compromisedejection fraction. Products provided as a combined preparation include acomposition comprising the compound disclosed herein and the othertherapeutic agent(s) together in the same pharmaceutical composition, orthe compound disclosed herein and the other therapeutic agent(s) inseparate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound as disclosed herein and another therapeuticagent(s). Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable carrier, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound disclosed herein. In one embodiment, the kit comprises meansfor separately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

Accordingly, the invention provides the use of a compound as disclosedherein for treating a disease or condition mediated by the cardiacsarcomere wherein the medicament is prepared for administration withanother therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or condition mediatedby the cardiac sarcomere, wherein the medicament is administered with acompound as disclosed herein. In another aspect, the invention providesthe use of a compound as disclosed herein for treating a heart failurehaving reduced or compromised ejection fraction wherein the medicamentis prepared for administration with another therapeutic agent. Theinvention also provides the use of another therapeutic agent fortreating heart failure having reduced or compromised ejection fraction,wherein the medicament is administered with a compound as disclosedherein.

The invention also provides a compound as disclosed herein for use in amethod of treating a disease or condition mediated by the cardiacsarcomere or in the treating of heart failure having reduced orcompromised ejection fraction, wherein the compound is prepared foradministration with another therapeutic agent. The invention alsoprovides another therapeutic agent for use in a method of treating adisease or condition mediated by the cardiac sarcomere or in thetreating of heart failure having reduced or compromised ejectionfraction, wherein the other therapeutic agent is prepared foradministration with a compound as disclosed herein. The invention alsoprovides a compound as disclosed herein for use in a method of treatinga disease or condition mediated by the cardiac sarcomere or in thetreating of heart failure having reduced or compromised ejectionfraction, wherein the compound is administered with another therapeuticagent. The invention also provides another therapeutic agent for use ina method of treating a disease or condition mediated by the cardiacsarcomere or in the treating of heart failure having reduced orcompromised ejection fraction, wherein the other therapeutic agent isadministered with a compound as disclosed herein.

The invention also provides the use of a compound as disclosed hereinfor treating a disease or condition mediated by the cardiac sarcomere orin the treating of heart failure having reduced or compromised ejectionfraction wherein the patient has previously (e.g. within 24 hours) beentreated with another therapeutic agent. The invention also provides theuse of another therapeutic agent for treating a disease or conditionmediated by the cardiac sarcomere or in the treating of heart failurehaving reduced or compromised ejection fraction wherein the patient haspreviously (e.g. within 24 hours) been treated with a compound asdisclosed herein.

The pharmaceutical compositions can be administered alone or incombination with other molecules known to have a beneficial effect onheart failure including molecules capable of increasing thecontractility of the heart and/or increasing the ejection fraction inpatients suffering from or susceptible to heart failure.

A combination therapy regimen may be additive, or it may producesynergistic results (e.g., increases in cardiac contractility orincreased cardiac ejection fraction which is more than expected for thecombined use of the two agents). In some embodiments, the presentinvention provide a combination therapy for preventing and/or treatingheart failure or more particularly systolic heart failure disease asdescribed above with a compound of the invention and a secondtherapeutic agent. Suitable additional active agents include, forexample: therapies that retard the progression of heart failure bydown-regulating neurohormonal stimulation of the heart and attempt toprevent cardiac remodeling (e.g., ACE inhibitors or P-blockers);therapies that improve cardiac function by stimulating cardiaccontractility (e.g., positive inotropic agents, such as the P-adrenergicagonist dobutamine or the phosphodiesterase inhibitor milrinone);therapies that reduce cardiac preload (e.g., diuretics, such asfurosemide), agents that reduce afterload such as nephrilysininhibitors/angiotensin receptor blockers, as well as drugs that slowheart rate, such as ivabradine; angiotensin receptor blockers (e.g.,without nephrilysin inhibitors); aldosterone antagonists (e.g.spironolactone, eplerenone); hydralizine-nitrates; and digoxin. Suitableadditional active agents also include, for example, agents that improvemitochondrial function.

In one embodiment, the invention provides a method of modulatingactivity of the cardiac sarcomere in a subject, wherein the methodcomprises administering to the subject a therapeutically effectiveamount of the compound according to the definition of Formula (I). Theinvention further provides methods of modulating the activity of thecardiac sarcomere in a subject by administering a compound as disclosedherein which bind to the Troponin C/Troponin I interface to increaseactivity of the cardiac sarcomere, wherein the method comprisesadministering to the subject a therapeutically effective amount of thecompound as disclosed herein.

In one embodiment, the invention provides a compound as disclosedherein, for use as a medicament.

In one embodiment, the invention provides the use of a compound asdisclosed herein for the treatment of a disorder or disease in a subjectcharacterized by reduced cardiac function. In particular, the inventionprovides the use of a compound as disclosed herein for the treatment ofa disorder or disease mediated by reduced cardiac sarcomere function,e.g., heart failure or more particularly systolic heart failure.

In one embodiment, the invention provides the use of a compound asdisclosed herein in the manufacture of a medicament for the treatment ofa disorder or disease in a subject characterized by reduced cardiacfunction. More particularly in the manufacture of a medicament for thetreatment of a disease or disorder in a subject characterized by reducedcardiac sarcomere function, e.g., heart failure or more particularlysystolic heart failure.

In one embodiment, the invention provides the use of a compound asdisclosed herein for the treatment of a disorder or disease in a subjectcharacterized by reduced cardiac function. More particularly, theinvention provides uses of the compounds provided herein in thetreatment of a disease or disorder characterized by reduced cardiacsarcomere function, e.g., heart failure or more particularly systolicheart failure. In certain embodiments, the use is in the treatment of adisease or disorder is selected from heart failure or systolic heartfailure.

In a specific embodiment, the present invention provides use of thecompounds of the invention for treating or preventing heart failure orsystolic heart failure. In certain embodiments, patients who arecurrently asymptomatic but are at risk of developing a symptomatic heartfailure or systolic heart failure are suitable for administration with acompound of the invention. The use in treating or preventing heartfailure or systolic heart failure include, but are not limited to, usesin treating or preventing one or more symptoms or aspects of heartfailure selected from reduced heart contractility and reduced ejectionfraction.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure materials.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade (° C.). If not mentioned otherwise, allevaporations are performed under reduced pressure, typically betweenabout 15 mm Hg and 100 mm Hg (20-133 mbar). The structure of finalproducts, intermediates and starting materials is confirmed by standardanalytical methods, e.g., microanalysis and spectroscopiccharacteristics, e.g., MS, IR, NMR. Abbreviations used are thoseconventional in the art.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art.

ABREVIATIONS FULL NAME DAST Diethylaminosulfur trifluoride DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIPEAN,N-Diisopropylethylamine, or Hünig

base DMF Dimethylformamide EDC N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaFLuorophosphate HMPT Tris(dimethylamino)phosphineHOBT Hydroxybenzotriazole HPLC High-performance liquid chromatographyMCPBA meta-Chloroperoxybenzoic acid MPLC Medium pressure liquidchromatography MTBE Methyl tert-butyl ether NMP N-Methyl-2-pyrrolidoneRT Room temperature (~23° C.) TBAF Tetra-n-butylammonium fluoride TBTU2-(1H-Benzotriazole-1-yl)-1,1,3,3- tetramethylaminium tetrafluoroborateTFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride

Intermediate 1.0: Preparation of((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-D-proline

Step 1: Preparation of tert-butyl(S)-3-((R)-2-((benzyloxy)carbonyl)pyrrolidine-1-carbonyl)piperidine-1-carboxylate

To a 0° C. solution of(S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (71 g, 310 mmol,Combi-Blocks, Inc.) in DCM (750 mL), was added TBTU (99 g, 310 mmol) jby the addition of DIPEA (151 mL, 867 mmol). The mixture was allowed tostir at 0° C. for 10 minutes then (R)-benzylpyrrolidine-2-carboxylatehydrochloride (73 g, 302 mmol, Sibian) was added in single portion.After an additional 5 minutes at 0° C., the reaction mixture was allowedto warm to rt and stirred for 2 h. The mixture was diluted with DCM (200mL) and quenched with saturated aqueous NaHCO₃ solution. The organicswere washed with saturated aqueous NH₄Cl, dried over anhydrous Na₂SO₄,filtered, and concentrated. The crude material was purified by MPLCusing silica gel (230-400 mesh) and eluted with 100% DCM to affordtert-butyl(S)-3-((R)-2-((benzyloxy)-carbonyl)pyrrolidine-1-carbonyl)piperidine-1-carboxylate(90 g) as a colorless gum. ¹H NMR (400 MHz, chloroform-d) δ 7.41-7.31(m, 5H), 5.22 (d, J=12.3 Hz, 1H), 5.11 (d, J=12.3 Hz, 1H), 4.55 (dd,J=8.7, 3.9 Hz, 1H), 4.15 (s, 2H), 3.75-3.55 (m, 2H), 2.87 (s, 1H), 2.70(s, 1H), 2.51 (br s, 1H), 2.20 (q, J=9.6, 6.9 Hz, 2H), 2.10-1.90 (m,4H), 1.71 (d, J=13.9 Hz, 2H), and 1.47 (m, 10H). LCMS-ESI (POS.) m/z:417.0 (M+H)+.

Step 2: Preparation of benzyl ((S)-piperidine-3-carbonyl)-D-prolinatehydrochloride

To a 0° C. solution of tert-butyl(S)-3-((R)-2-((benzyloxy)carbonyl)pyrrolidine-1-carbonyl)piperidine-1-carboxylate (128 g, 307 mmol) in 1,4-dioxane (100 mL) wasslowly added 4M HCl in dioxane (990 mL, 3.96 mol). The solution wasallowed to warm to rt and stirred for 3 h, concentrated under reducedpressure, and azeotroped with toluene (200 mL×3). The residue was thentriturated with petroleum ether (300 mL) to afford benzyl((S)-piperidine-3-carbonyl)-D-prolinate hydrochloride (105 g) as whitesolid. ¹H NMR (400 MHz, chloroform-d) δ 9.81 (s, 1H), 9.14 (s, 1H),7.39-7.31 (m, 5H), 5.19 (d, J=12.3 Hz, 1H), 5.07 (d, J=12.3 Hz, 1H),4.53 (dd, J=8.6, 4.1 Hz, 1H), 3.69 (dt, J=10.3, 6.9 Hz, 1H), 3.61 (dt,J=9.9, 6.5 Hz, 1H), 3.44-3.34 (m, 2H), 3.26-3.16 (m, 2H), 2.95 (m, 1H),2.65 (s, 1H), 2.22 (ddt, J=14.8, 8.7, 6.1 Hz, 1H), 1.99 (dt, J=9.0, 5.2Hz, 4H), 1.87 (s, 1H), and 1.66 (dq, J=9.9, 5.4, 4.5 Hz, 1H). LCMS-ESI(POS.) m/z: 317.2 (M+H)+.

Step 3: Preparation of benzyl((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-D-prolinate

To a solution of benzyl ((S)-piperidine-3-carbonyl)-D-prolinatehydrochloride (77 g, 218 mmol) in DCM (570 mL) at rt was added DIPEA(152 mL, 873 mmol) and then 3-cyanoazetidine-1-sulfonyl chloride (59.1g, 327 mmol, Synthonix). After stirring at rt for 3 h, the mixture wasdiluted with saturated aqueous NH₄Cl (500 mL) and DCM (300 mL). Theorganic layer was separated and washed successively with 1N HCl solution(100 mL) and brine (500 mL). After drying over anhydrous Na₂SO₄, thesuspension was filtered and concentrated under reduced pressure. Thecrude material was purified by MPLC using silica gel (230-400 mesh) andeluted with 1% methanol in DCM, to provide benzyl((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-D-prolinate(74 g) as brown oil. ¹H NMR (300 MHz, chloroform-d) δ 7.44-7.32 (m, 5H),5.28-5.17 (m, 1H), 5.11 (d, J=12.3 Hz, 1H), 4.54 (dd, J=8.6, 3.7 Hz,1H), 4.42-4.34 (m, 1H), 4.13-4.05 (m, 4H), 3.83-3.72 (m, 2H), 3.70-3.59(m, 2H), 3.48-3.35 (m, 1H), 3.04-2.94 (m, 1H), 2.72 (dtt, J=18.8, 11.4,3.5 Hz, 2H), 2.22 (tdd, J=10.7, 6.6, 4.0 Hz, 1H), 2.02 (dddd, J=14.3,10.5, 6.6, 4.5 Hz, 4H), and 1.70-1.58 (m, 2H). LCMS-ESI (POS.) m/z:461.4 (M+H)+.

Step 4: Preparation of((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-D-proline,Intermediate 1.0

To a solution of benzyl((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-D-prolinate(72 g, 156 mmol) in methanol (750 mL) at rt was added 10% Pd/C (8.32 g,78 mmol). The resulting mixture was stirred under hydrogen atmosphere (1atm) for 3 h. The mixture was then filtered and the reaction wassubjected to another lot of 10% Pd/C (8.32 g, 78 mmol). After 3 h, thereaction mixture was filtered through a pad of Celite and the filtratewas concentrated under reduced pressure to afford((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-D-proline(51 g) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (s, 1H),4.21 (dd, J=8.8, 4.2 Hz, 1H), 4.09-4.03 (m, 2H), 3.94 (ddd, J=8.0, 5.9,3.0 Hz, 2H), 3.84-3.76 (m, 1H), 3.56 (dt, J=18.1, 5.8 Hz, 4H), 2.90-2.74(m, 2H), 2.65 (td, J=7.4, 3.6 Hz, 1H), 2.24-2.08 (m, 1H), 1.97-1.77 (m,4H), 1.74-1.66 (m, 1H), and 1.54-1.36 (m, 2H). LCMS-ESI (POS.) m/z:371.0 (M+H)+.

The intermediates in the following table were synthesized following theprocedure described for Intermediate 1.0 using known starting materialreplacements as described.

TABLE 1 Intermediate Reagents Structure, Name and Data 1.13-(methylsulfonyl)azetidine hydrochloride (Advanced Chem Blocks)

(R)-1-((S)-1-((3-(methylsulfonyl)azetidin-1-yl)sulfonyl)piperidine-3-carbonyl)pyrrolidine-2- carboxylic acid.LCMS-ESI (POS.) m/z: 424.0 (M + H)+. 1.2 3-methylazetidin-3-ol-hydrochloride (Astatech)

(R)-1-((S)-1-((3-hydroxy-3-methylazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)pyrrolidine-2- carboxylic acid.LCMS-ESI (POS.) m/z: 376.2 (M + H)+. 1.3 (S)-1-(tert-butoxycarbonyl)-4-((3-cyanoazetidin-1- yl)sulfonyl)piperazine-2- carboxylic acid (Arkpharm)

(R)-1-((S)-1-(tert-butoxycarbonyl)-4-((3-cyanoazetidin-1-yl)sulfonyl)piperazine-2-carbonyl)pyrrolidine-2-carboxylic acid. LCMS-ESI (POS.) m/z: 472.2 (M +H)+.

Intermediate 2.0: Preparation of(S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carboxylic Acid

(S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carboxylic Acid,Intermediate 2.0

To a stirred solution of (S)-piperidine-3-carboxylic acid (90.0 g, 697mmol, Combi-Blocks, Inc.) in THF (1 L) and water (1 L) at rt was addedNa₂SO₄ (222 g, 2.10 mol), and 3-cyanoazetidine-1-sulfonyl chloride (138g, 767 mmol, Synthonix). After stirring at rt for 18 h, the reaction wasquenched with water (250 mL) and extracted with ethyl acetate (2×1 L).The pH of the aqueous layer was adjusted to approximately 2 with 6N HCland then extracted with ethyl acetate (2×1.5 L). The combined organicextracts were washed with water (500 mL), saturated brine solution (500mL), dried over anhydrous Na₂SO₄, and concentrated under reducedpressure to provide(S)-1-((3-cyanoazetidin-1-yl)sulfonyl)-piperidine-3-carboxylic acid (141g) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.48 (s, 1H), 4.06 (s,2H), 3.96-3.93 (m, 2H), 3.79 (td, J=6.1, 3.1 Hz, 1H), 3.56 (dd, J=12.2,3.9 Hz, 1H), 3.38 (s, 1H), 2.99 (d, J=2.5 Hz, 1H), 2.90-2.84 (m, 1H),2.49 (m, 1H), 1.88 (q, J=4.5, 4.0 Hz, 1H), 1.70 (q, J=4.8 Hz, 1H), and1.51-1.45 (m, 2H).

Intermediate 3.0: Preparation of(3-((3-cyanoazetidin-1-yl)sulfonyl)benzoyl)-D-proline

Step 1: Preparation of azetidine-3-carbonitrile hydrochloride

To a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (300 g, 1.65mol, Pharma Blocks) in 1,4-dioxane (300 mL) at 0° C. was added 4M HCl indioxane (1.25 L, 5.0 mol). The mixture was allowed to warm to rt andstirred for an additional 4 h. The reaction mixture was thenconcentrated under reduced pressure and azeotroped with toluene (3×250mL). The residue was slurried with hexanes (500 mL) and dried under highvacuum to give azetidine-3-carbonitrile hydrochloride (195 g) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.87 (bs, 2H), 4.22-4.08 (m, 4H),4.05-3.95 (m, 1H).

Step 2: Preparation of 3-((3-cyanoazetidin-1-yl)sulfonyl)benzoic Acid,Intermediate 3.1

To a suspension of azetidine-3-carbonitrile hydrochloride (275 g, 2.32mol) in DCM (2.8 L) at 0° C. was added triethylamine (1.3 L, 9.28 mol).The mixture was stirred for 10 min at 0° C. then3-(chlorosulfonyl)benzoic acid (563 g, 2.56 mol, Arbor Chemicals) wasslowly added in portions over the period of 1 h (Caution: Exotherm). Thereaction mixture was stirred at rt for 3 h and then cooled to 0° C. andquenched with 1N aqueous HCl (4 L). The precipitate was collected byfiltration, washed with water (2 L) and dried under vacuum to give3-((3-cyanoazetidin-1-yl)sulfonyl)benzoic acid (475 g) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 13.65 (bs, 1H), 8.33 (d, J=7.8 Hz, 1H),8.26 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.87 (dd, J=8.1, 7.8 Hz, 1H), 4.02(dd, J=8.5, 5.8 Hz, 2H), 3.89 (dd, J=8.5, 5.8 Hz, 2H), 3.68-3.60 (m,1H). LCMS-ESI (NEG) m/z: 265.0 (M−H)−.

Step 3: Preparation of benzyl(3-((3-cyanoazetidin-1-yl)sulfonyl)benzoyl)-D-prolinate

To a solution of 3-((3-cyanoazetidin-1-yl)sulfonyl)benzoic acid (220 g,826 mmol) in DCM (2.2 L) at 0° C. was added TBTU (279 g, 868 mmol) andDIPEA (418 mL, 2396 mmol). After 10 min at 0° C., (R)-benzylpyrrolidine-2-carboxylate hydrochloride (200 g, 826 mmol, TCl) was addedand stirred at rt for 2 h. The reaction mixture was quenched with water(1 L) and extracted with DCM (2×1000 mL). The organic layer was washedconsecutively with 10% aqueous NaHCO₃ solution (500 mL) and brine (500mL). The organic layer was dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude material was adsorbed onto silica gel(60-120 mesh) and purified by column chromatography (silica gel, 230-400mesh) using 1% MeOH in DCM to give benzyl(3-((3-cyanoazetidin-1-yl)sulfonyl)benzoyl)-D-prolinate (210 g) as athick brown oil. ¹H NMR (400 MHz, chloroform-d): δ 8.04 (s, 1H), 7.92(d, J=8.0 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.68 (dd, J=8.0, 7.6 Hz, 1H),7.40-7.32 (m, 5H), 5.30-5.18 (m, 2H), 4.76-4.70 (m, 1H), 4.10-3.97 m,3H), 3.65 (dd, J=11.6, 5.3 Hz, 1H), 3.51 (dt, J=10.2, 6.4 Hz, 1H),3.37-3.30 (m, 1H), 2.50-2.29 (m, 1H), 2.10-1.88 (m, 4H). LCMS-ESI (POS.)m/z: 454.0 (M+H)+.

Step 4: Preparation of(3-((3-cyanoazetidin-1-yl)sulfonyl)benzoyl)-D-proline, Intermediate 3.0

A 5 L autoclave was charged with a solution of benzyl(3-((3-cyanoazetidin-1-yl)sulfonyl)benzoyl)-D-prolinate (140 g, 309mmol) in methanol (1.8 L). The autoclave was purged with nitrogen gasfor 5 min then 10% Pd/C (3.29 g) was added and the mixture was stirredunder hydrogen pressure (20 psi) at rt for 4 h. The reaction mixture wasfiltered through a bed of Celite and concentrated under reducedpressure. The crude material was then adsorbed onto silica gel (60-120mesh) and purified by column chromatography (silica gel, 230-400 mesh)using 3% MeOH in DCM to give(3-((3-cyanoazetidin-1-yl)sulfonyl)benzoyl)-D-proline (70 g) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 12.67 (bs, 1H), 8.00-7.76 (m, 4H),4.45-4.37 (m, 1H), 4.06-3.85 (m, 4H), 3.69-3.52 (m, 3H), 2.31-2.27 (m,1H), 2.01-1.87 (m, 3H). LCMS-ESI (NEG) m/z: 362.0 (M−H)−.

Intermediate 4.0: Preparation of (3-(methylsulfonyl)benzoyl)-D-proline

Preparation of (3-(methylsulfonyl)benzoyl)-D-proline, Intermediate 4.0

The above titled compound was made following the procedure described forthe synthesis of Intermediate 14.0 replacing3-(N,N-dimethylsulfamoyl)benzoic acid with 3-(methylsulfonyl)benzoicacid (Combi-Blocks, Inc.). LCMS-ESI (POS.). m/z: 298.2 (M+H)+.

Intermediate 5.0: Preparation of(1R,3R,5R)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid

Step 1: Preparation of (1R,3R,5R)-ethyl2-azabicyclo[3.1.0]hexane-3-carboxylate hydrochloride

A 100 mL round-bottom flask was charged with (1R,3R,5R)-2-tert-butyl3-ethyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.0 g, 3.92 mmol,Synthonix, Inc.) and DCM (13.0 mL). To that solution was added 4.0M HClin dioxane (4.90 mL, 19.6 mmol). After 2.5 hours at rt, the mixture wasconcentrated under reduced pressure and azeotroped with methanol (×2, 10mL) to give (1R,3R,5R)-ethyl 2-azabicyclo[3.1.0]hexane-3-carboxylatehydrochloride (0.751 g, 100%) as a foam. LCMS-ESI (POS.). m/z: 156.2(M+H)+.

Step 2: Preparation of (1R,3R,5R)-ethyl2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate

A 100 mL round-bottom flask was charged with (1R,3R,5R)-ethyl2-azabicyclo[3.1.0]hexane-3-carboxylate hydrochloride (0.75 g, 3.9 mmol)and DCM (20 mL). To that stirring solution at rt was added3-(methylsulfonyl)benzoic acid (1.2 g, 5.9 mmol, Combi-Blocks, Inc.),TBTU (1.9 g, 5.9 mmol) and DIPEA (3.4 mL, 19.6 mmol). After 24 hours,the reaction mixture was concentrated under reduced pressure. Theresulting oil was diluted with DCM, and purified by MPLC on silica gel,eluting with 0-50% ethyl acetate in heptane to provide (1R,3R,5R)-ethyl2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate(1.1 g, 83%). LCMS-ESI (POS.). m/z: 338.0 (M+H)+.

Step 3: Preparation of(1R,3R,5R)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid, Intermediate 5.0

To a 50 mL round-bottom flask was added (1R,3R,5R)-ethyl2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate(1.0 g, 3.0 mmol), lithium hydroxide (0.14 g, 14.8 mmol) in 1,4-dioxane(10 mL) and water (10 mL). The reaction mixture was stirred at rt for 1h, then diluted with water and acidified to pH=2 with 1N HCl. Themixture was extracted with 3:1 DCM/MeOH, and the combined organicextracts were washed with brine, dried over MgSO₄, filtered, andconcentrated under reduced pressure to afford(1R,3R,5R)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (0.81 g) as white solid. LCMS-ESI (POS.). m/z: 310.0 (M+H)+.

Intermediate 6.0: Preparation of3-((3-cyanoazetidin-1-yl)sulfonyl)-5-fluorobenzoic Acid

3-((3-cyanoazetidin-1-yl)sulfonyl)-5-fluorobenzoic acid, Intermediate6.0. A 40 mL pressure vial was charged with3-(chlorosulfonyl)-5-fluorobenzoic acid (500 mg, 2.10 mmol, Enamine) and3-cyanoazetidine hydrochloride (497 mg, 4.19 mmol, Synthonix, Inc.). Tothat mixture was added DCM (10.5 mL) followed by triethylamine (1.17 mL,8.38 mmol). After 2 hours at rt, the mixture was transferred to aseparatory funnel and the pH was adjusted to ˜10 using saturated aqueoussolution NaHCO₃. The layers were separated and the aqueous was carefullyacidified with concentrated HCl (pH=3) upon which a white solidprecipitated from the solution. The solid was collected by filtrationand lyophilized to give3-((3-cyanoazetidin-1-yl)sulfonyl)-5-fluorobenzoic acid (349 mg) as awhite solid. 1H NMR (500 MHz, DMSO-d₆) δ ppm 3.64 (tt, J=8.94, 5.86 Hz,1H) 3.96 (dd, J=8.69, 5.84 Hz, 2H) 4.06 (t, J=8.82 Hz, 2H) 8.03 (dt,J=7.85, 1.98 Hz, 1H) 8.07-8.11 (m, 2H) 13.92 (brs, 1H). LCMS-ESI (POS.)m/z: 285.2 (M+H)+.

Intermediate 7.0: Preparation of Sodium(S)-4-((3-cyanoazetidin-1-yl)sulfonyl)morpholine-2-carboxylate

Sodium (S)-4-((3-cyanoazetidin-1-yl)sulfonyl)morpholine-2-carboxylate,Intermediate 7.0

A 100 mL round-bottom flask was charged with (S)-morpholine-2-carboxylicacid hydrochloride (1.5 g, 8.95 mmol, Ark Pharma, Inc.) and a 1:1mixture of THF (15 mL) and water (15 mL). To that rt solution was addedNa₂CO₃, anhydrous (2.85 g, 27.0 mmol) followed by3-cyanoazetidine-1-sulfonyl chloride (1.94 g, 10.7 mmol, Synthonix,Inc). The turbid solution was stirred overnight at rt and thentransferred into a separatory funnel and diluted with water and ethylacetate. The aqueous layer was extracted with ethyl acetate (×3) andthen transferred into an Erlenmeyer flask and acidified to a pH of 2using 1.0 N HCl. The aqueous was then extracted with ethyl acetate (×4,20 mL) to yield 1.41 g (5.4 mmol). The sticky oil was then dissolved inwater and sodium hydroxide. While at rt, 1.0 N NaOH (5.4 mL, 5.4 mmol)was added and the mixture was stirred for 30 minutes and thenlyophilized overnight to give sodium(S)-4-((3-cyanoazetidin-1-yl)sulfonyl)morpholine-2-carboxylate (1.49 g)as a fluffy white solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 4.08 (q, J=7.83Hz, 2H), 3.92-3.97 (m, 2H), 3.86-3.91 (m, 1H), 3.77-3.86 (m, 1H), 3.54(br d, J=12.07 Hz, 1H), 3.45 (dd, J=9.73, 2.85 Hz, 1H), 3.33-3.40 (m,1H), 3.21 (br d, J=11.68 Hz, 1H), 2.77-2.84 (m, 1H), 2.69-2.76 (m, 1H).LCMS-ESI (POS.) m/z: 298.2 (M+Na)+.

Intermediate 8.0: Preparation of(R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl) methanaminehydrochloride

Step 1: Preparation of 2,5-difluoro-4-(trifluoromethyl)benzaldehyde

To a solution of 1-bromo-2,5-difluoro-4-(trifluoromethyl)benzene (130 g,498 mmol, Oakwood, Inc.) in THF (1.3 L) was added isopropylmagnesiumchloride (2M solution in THF, 274 mL, 548 mmol) drop-wise under nitrogenatmosphere at −45° C. The reaction mixture was stirred at −45° C. for 30min and then DMF (174 mL, 2.24 mol) was slowly added and stirred for 20min. The reaction mixture was allowed to warm to 0° C. and quenched withsaturated aqueous NH₄Cl solution (500 mL), diluted with water (1.5 L),and extracted with EtOAc (3×2 L). The organic layer was washed withbrine (2.0 L) and dried over Na₂SO₄, filtered, and concentrated underreduced pressure to give 2,5-difluoro-4-(trifluoromethyl)benzaldehyde(65 g) as a colorless oil. ¹H NMR (400 MHz, chloroform-d): δ 10.38 (s,1H), 7.71 (dd, J=9.2, 5.2 Hz, 1H), 7.52 (dd, J=9.2, 5.2 Hz, 1H).

Step 2: Preparation of(S,E)-N-(2,5-difluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide

To a suspension of copper(II) sulfate (228 g, 1.43 mol) and2-methylpropane-2-sulfinamide (130 g, 1.07 mol) in 1,2-dichloroethane(2.2 L) was added 2,5-difluoro-4-(trifluoromethyl)benzaldehyde (150 g,0.714 mol) at rt. The reaction mixture was heated 80° C. and stirred for18 h. The mixture was filtered through a pad of Celite and the filtercake was washed with 1,2-dichloroethane (500 mL). The filtrate wasconcentrated under reduced pressure. The crude residue was absorbed ontoa plug of silica gel (60-120 mesh) and purified by column chromatography(silica gel, 60-120 mesh), eluting with 4% to 10% EtOAc in hexanes toprovide(S,E)-N-(2,5-difluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide(195 g) as a pale brown viscous oil. ¹H NMR (400 MHz, chloroform-d):68.88 (s, 1H), 7.85 (dd, J=9.6, 5.6 Hz, 1H), 7.47 (dd, J=9.2, 5.2 Hz,1H), 1.31 (s, 9H).

Step 3: Preparation of(S)—N—((S)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamideand(S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide

A solution of(S,E)-N-(2,5-difluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide(195 g, 622 mmol) in DCM (3.6 L) was cooled to −78° C.Cyclopropylmagnesium bromide (0.5M in THF, 1.87 L, 934 mmol) was thenadded dropwise over 1 h. The reaction mixture was stirred at −78° C. foran additional 1 h and allowed to warm to rt over 2 h. The rt reactionmixture was quenched with saturated aqueous NH₄Cl solution (700 mL) andextracted with DCM (3×700 mL). The organic layer was washed with water(500 mL), brine (500 mL), dried over Na₂SO₄, and concentrated underreduced pressure. The crude residue was absorbed onto a plug of silicagel (60-120 mesh) and purified by column chromatography (silica gel,230-400 mesh) using 5-15% EtOAc in hexanes. The first eluting peak(minor) was assigned as(S)—N—((S)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide(16 g) and collected as a brown oil. ¹H NMR (400 MHz, DMSO-d₆): δ7.78-7.65 (m, 2H), 5.95 (d, J=8.0 Hz, 1H), 3.87 (dd, J=8.0, 7.4 Hz, 1H),1.27-1.20 (m, 1H), 1.12 (s, 9H), 0.65-0.60 (m, 1H), 0.52-0.46 (m, 2H),0.37-0.33 (m, 1H). LCMS-ESI (POS.) m/z: 356.1 (M+H)+. The second elutingpeak (major) was assigned as(R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide(95 g) and collected as a brown oil. ¹H NMR (400 MHz, DMSO-d₆): δ7.78-7.70 (m, 2H), 5.73 (d, J=6.8 Hz, 1H), 3.87 (dd, J=8.0, 6.8 Hz, 1H),1.32-1.27 (m, 1H), 1.08 (s, 9H), 0.65-0.61 (m, 1H), 0.52-0.46 (m, 2H),0.37-0.33 (m, 1H). LCMS-ESI (POS.) m/z: 356.2 (M+H)⁺. Thestereochemistry was assigned based on literature precedent (see Ellman,J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984).

Step 4: Preparation of(R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methanaminehydrochloride, Intermediate 8.0

To a solution of(S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide(95 g, 268 mmol) in methanol (450 mL) was added HCl (4M solution indioxane, 134 mL, 535 mmol) at 0° C. and stirred at rt for 2 h. Thereaction mixture was concentrated under reduced pressure and azeotropedwith DCM (500 mL). The residual solid was triturated with diethyl ether(500 mL) and filtered and dried under vacuum to give(R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methanaminehydrochloride (73 g) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆):δ9.10 (s, 3H), 8.19 (dd, J=10.8, 5.6 Hz, 1H), 7.88 (dd, J=8.4, 6.4 Hz,1H), 3.87 (d, J=8.8 Hz, 1H), 1.46-1.38 (m, 1H), 0.78-0.68 (m, 2H),0.57-0.53 (m, 1H), 0.39-0.33 (m, 1H). LCMS-ESI (POS.) m/z: 252.1 (M+H)+.

The compounds set forth in the following table were synthesizedfollowing the procedure described for Intermediate 8.0 starting fromStep 1 or Step 2 using known starting material replacements. Thediastereomeric ratios ranged from 4:1 to >95:5 favoring the desiredisomer. The stereochemistry was tentatively assigned based on literatureprecedent (see Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.2002, 35, 984).

TABLE 2 Intermediate Reagents Structure, Name and Data 9.0 4-chloro-2-fluorobenzaldehyde (Matrix Scientific) and 3.4M methylmagnesium bromidein 2-MeTHF

(R)-1-(4-chloro-2-fluorophenyl)ethanamine hydrochloride. ¹H NMR (500MHz, DMSO-d₆) δ ppm 8.50 (3H, br s) 7.66 (1H, br t, J = 8.15 Hz) 7.55(1H, dd, J = 10.38, 1.95 Hz) 7.43 (1H, dd, J = 8.37, 1.88 Hz) 4.60 (1H,q, J = 6.83 Hz) 1.50 (3H, d, J = 6.88 Hz). LCMS (POS.) m/z: 157.2 (M −NH₂)+. 9.1 3.5- difluorobenzaldehyde and 3.4M methyl magnesium bromidein 2-MeTHF

(R)-1-(3,5-difluorophenyl)ethanamine hydrochloride. LCMS (POS.) m/z:141.2 (M − NH₂)+. 9.2 4-chloro-2,5- difluorobenzaldehyde (Combi-Blocks,Inc.)

(R)-(4-chloro-2,5 difluorophenyl)(cyclopropyl)methanamine hydrochloride.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.88 (br s, 3H), 7.99 (dd, J = 9.85,6.32 Hz, 1H), 7.77 (dd, J = 9.43, 6.22 Hz, 1H), 3.79 (br d, J = 8.50 Hz,1H), 1.35-1.44 (m, 1H), 0.64-0.72 (m, 2H), 0.48-0.57 (m, 1H), 0.28-0.35(m, 1H). LCMS (POS.) m/z: 201.2 (M − NH₂)+. 9.3 3-fluoro-4-(trifluoromethyl) benzaldehyde (Combi-Blocks, Inc.)

(R)-cyclopropyl(3-fluoro-4- (trifluoromethyl)phenyl)methanaminehydrochloride. ¹H NMR (500 MHz, chloroform-d) δ ppm 9.09-9.34 (m, 3H),7.65-7.71 (m, 1H), 7.55 (br d, J = 10.64 Hz, 1H), 7.42-7.47 (m, 1H),3.56-3.67 (m, 1H), 1.40-1.50 (m, 1H), 0.71-0.82 (m, 3H), 0.46 (br dd, J= 8.63, 3.70 Hz, 1H. LCMS (POS.) m/z: 217.2 (M − NH₂)+. 9.4 4-chloro-2-fluorobenzaldehyde (Matrix Scientific)

(R)-(4-chloro-2-fluorophenyl)(cyclopropyl)methanamine hydrochloride. ¹HNMR (500 MHz, chloroform-d) δ ppm 9.16 (br d, J = 1.56 Hz, 3H) 7.74 (t,J = 8.17 Hz, 1H) 7.23-7.28 (m, 2H) 3.94-4.03 (m, 1H) 1.50-1.59 (m, 1H)0.77-0.87 (m, 2H) 0.68-0.76 (m, 1H) 0.47-0.56 (m, 1H). LCMS-ESI (POS.).m/z: 183.2 (M − NH₂)+. 9.5 2-fluoro-4- (trifluoromethyl) benzaldehyde(Combi-Blocks, Inc.)

(R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methanaminehydrochloride. ¹H NMR (500 MHz, chloroform-d) δ ppm 9.03-9.31 (m, 3H),7.86 (t, J = 7.46 Hz, 1H), 7.37-7.46 (m, 2H), 3.95 (br dd, J = 9.54,5.25 Hz, 1H), 1.41-1.50 (m, 1H), 0.68-0.76 (m, 2H), 0.60-0.68 (m, 1H),0.46 (dq, J = 9.93, 5.17 Hz, 1H). LCMS-ESI (POS.). m/z: 217.2 (M −NH₂)+. 9.6 4-(trifluoromethyl) benzaldehyde

(R)-cyclopropyl(4-(trifluoromethyl)phenyl)methanamine hydrochloride.LCMS-ESI (POS.). m/z: 199.0 (M − NH₂)+. 9.7 2-fluoro-4-(trifluoromethyl) benzaldehyde (Combi-Blocks, Inc.) and 4-cyclobutylmagnesium chloride, 0.5M in THF (Oakwood Products, Inc.).

(R)-cyclobutyl(2-fluoro-4-(trifluoromethyl)phenyl)methanaminehydrochloride. ¹H NMR (500 MHz, chloroform-d) δ ppm 8.92 (br s, 3H) 7.70(t, J = 7.46 Hz, 1H) 7.43 (d, J = 8.30 Hz, 1H) 7.39 (d, J = 3.73 Hz, 1H)4.55 (br d, J = 5.06 Hz, 1H) 2.88- 3.00 (m, 1H) 1.99-2.16 (m, 2H)1.79-1.94 (m, 3H) 1.66-1.78 (m, 1H). LCMS-ESI (POS.). m/z: 248.2 (M +H)+. 9.8 4-chloro-3,5- difluorobenzaldehyde (Aurum Pharmatech, LLC.)

(R)-(4-chloro-3,5-difluorophenyl)(cyclopropyl)methanamine hydrochloride.¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.60 (br s, 3H), 7.57 (s, 1H), 7.55 (s,1H), 3.64 (br d, J = 9.99 Hz, 1H), 1.25-1.34 (m, 1H), 0.66-0.74 (m, 1H),0.59 (dq, J = 9.63, 5.05 Hz, 1H, 0.49-0.56 (m, 1H), 0.44 (dq, J =9.83,4.94 Hz, 1H). LCMS-ESI (POS.). m/z: 201.2 (M − NH₂)+. 9.92,5-difluoro-4- methoxybenzaldehyde (Combi-Blocks, Inc.).

(R)-cyclopropyl(2,5-difluoro-4-methoxyphenyl)methanamine hydrochloride.¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.29- 8.73 (m, 3H), 7.55-7.72 (m, 1H),7.22 (br dd, J = 11.48, 7.33 Hz, 1H), 3.87 (s, 3H), 3.74 (br d, J = 9.34Hz, 1H), 1.31-1.39 (m, 1H), 0.68 (br s, 1H), 0.60 (br d, J = 4.41 Hz,1H), 0.52 (br d, J = 4.41 Hz, 1H), 0.28 (br dd, J = 9.67, 5.00 Hz, 1H).LCMS-ESI (POS.). m/z: 197.2 (M − NH₂)+. 9.10 4- (difluoromethyl)benzaldehyde (Enamine, Ltd.) and 3.4M methylmagnesium bromide in 2-MeTHF

(R)-1-(4-(difluoromethyl)phenyl)ethan-1-amine hydrochloride. LCMS (POS.)m/z: 172.2 (M + H)+. 9.11 2-fluoro-4- methylbenzaldehyde (AstaTech) and3.4M methylmagnesium bromide in 2-MeTHF

(R)-1-(2-fluoro-4-methylphenyl)ethan-1-amine hydrochloride. ¹H NMR (500MHz, chloroform-d) δ ppm 8.63-8.99 (m, 3H), 7.44-7.58 (m, 1H), 6.87-7.02(m, 2H), 4.66-4.83 (m, 1H), 2.35 (s, 3H), 1.67-1.74 (m, 3H). LCMS (POS.)m/z: 137.2 (M − NH₂)+. 9.12 4-(trifluoromethyl) benzaldehyde and 3.0Methylmagnesium bromide in diethyl ether

(S)-1-(4-(trifluoromethyl)phenyl)propan-1-amine hydrochloride. LCMS(POS.) m/z: 204.2 (M + H)+. 9.13 4-(trifluoromethyl) benzaldehyde and3.0M ethylmagnesium bromide in diethyl ether

(R)-1-(4-(trifluoromethyl)phenyl)propan-1-amine hydrochloride. LCMS(POS.) m/z: 204.2 (M + H)+. 9.14 4-(trifluoromethyl) benzaldehyde

(S)-cyclopropyl(4-(trifluoromethyl)phenyl) methanamine hydrochloride.LCMS (POS.) m/z: 199.2 (M − NH₂)+. 9.15 2-fluoro-4- (trifluoromethyl)benzaldehyde (Sigma- Aldrich) and 3.0M ethylmagnesium bromide in diethylether

(S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)propan-1-amine hydrochloride.LCMS (POS.) m/z: 222.2 (M + H)+. 9.16 2-fluoro-4- (trifluoromethyl)benzaldehyde and 3.0M ethylmagnesium bromide in diethyl ether

(R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)propan-1-amine hydrochloride.LCMS (POS.) m/z: 222.2 (M + H)+. 9.17 2-fluoro-4- (trifluoromethyl)benzaldehyde and 1.0M isopropylmagnesium bromide in THF

(S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropan-1- aminehydrochloride. LCMS (POS.) m/z: 236.2 (M + H)+. 9.18 2-fluoro-4-(trifluoromethyl) benzaldehyde and 1.0M isopropylmagnesium bromide inTHF

(R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropan-1- aminehydrochloride. LCMS (POS.) m/z: 236.2 (M + H)+. 9.19 4-chloro-3-fluorobenzaldehyde (Combi-Blocks Inc.) and 3.0M ethylmagnesium bromidein diethyl ether

(S)-1-(4-chloro-3-fluorophenyl)propan-1-amine hydrochloride. LCMS (POS.)m/z: 171.0 (M − NH₂)+. 9.20 4-chloro-3- fluorobenzaldehyde (Combi-BlocksInc.) and 3.0M ehtylmagnesium bromide in diethyl ether

(R)-1-(4-chloro-3-fluorophenyl)propan-1-amine hydrochloride. LCMS (POS.)m/z: 171.2 (M − NH₂)+. 9.21 3,5- difluorobenzaldehyde and 3.0Methylmagnesium bromide in diethyl ether

(S)-1-(3,5-difluorophenyl)propan-1-amine hydrochloride. LCMS (POS.) m/z:172.2 (M + H)+. 9.22 3,5- difluorobenzaldehyde and 3.0M ethylmagnesiumbromide in diethyl ether

(R)-1-(3,5-difluorophenyl)propan-1-amine hydrochloride. LCMS (POS.) m/z:172.2 (M + H)+. 9.23 4-chloro-2,5- difluorobenzaldehyde (Combi-Blocks)and 3.0M ethylmagnesium bromide in diethyl ether

(R)-1-(4-chloro-2,5-difluorophenyl)propan-1-amine hydrochloride. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 8.51- 8.81 (m, 3H), 7.76-7.89 (m, 2H).4.29-4.45 (m, 1H), 1.94- 2.06 (m, 1H), 1.74-1.92 (m, 1H). 0.66-0.83 (m,3H). LCMS (POS.) m/z: 206.2 (M + H)+. 9.24 4-chloro-3-fluorobenzaldehyde (Combi-Blocks)

(R)-(4-chloro-3-fluorophenyl)(cyclopropyl) methanamine hydrochloride. ¹HNMR (500 MHz, chloroform-d) δ ppm 8.81-9.15 (m, 3H), 7.38-7.50 (m, 2H),7.27 (br s, 1H), 3.65-3.73 (m, 1H), 3.52-3.56 (m, 1H), 0.30-0.83 (m,4H). 9.25 4-chloro-2,5- difluorobenzaldehyde (Combi-Blocks) and 3.4Mmethylmagnesium bromide with 2-MeTHF

(R)-1-(4-chloro-2,5-difluorophenyl)ethan-1-amine hydrochloride. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 8.77 (br s, 3H), 7.82-7.93 (m, 1H), 7.72-7.82(m, 1H), 4.53-4.66 (m, 1H), 1.44-1.59 (m, 3H). 9.26 1-bromo-4-(difluoromethyl)-2- fluorobenzene and 3.4M methylmagnesium bromide with2-MeTHF

(R)-1-(4-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride. ¹HNMR (500 MHz, chloroform-d) δ ppm 8.27-8.96 (m, 3H), 7.75-7.84 (m, 1H),7.00-7.10 (m, 1H), 6.84-6.92 (m, 1H), 6.18-6.49 (m, 1H), 4.66 (q, J =6.83 Hz, 1H), 1.48-1.66 (m, 3H). LCMS (POS.) m/z: 173.2 (M − NH₂)+. 9.271-bromo-4- (difluoromethy)-2- fluorobenzene

(R)-cyclopropyl(4-(difluoromethyl)-2- fluorophenyl)methanaminehydrochloride. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.58-8.94 (m, 3H),7.86-8.00 (m, 1H), 7.48-7.64 (m, 2H), 6.92-7.29 (m, 1H), 3.79-3.96 (m,1H), 3.27-3.51 (m, 1H), 1.31-1.48 (m, 1H), 0.60-0.79 (m, 2H), 0.45-0.58(m, 1H), 0.26-0.40 (m, 1H). 9.28 2-fluoro-4- (trifluoromethyl)benzaldehyde with 3.4M methylmagnesium bromide in 2-MeTHF

(R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethanamine hydrochloride. LCMS(POS.) m/z: 208.2 (M + H)+. 9.29 2-methoxy-4- (trifluoromethyl)benzaldehyde (Alfa Aesar)

(R)-cyclopropyl(2-methoxy-4-(trifluoromethyl)phenyl) methanaminehydrochloride. LCMS (POS.) m/z: 229.0 (M − NH₂)+. 9.30 3-fluoro-4-methylbenzaldehyde

(R)-cyclopropyl(3-fluoro-4-methylphenyl) methanamine hydrochloride. ¹HNMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 3H), 7.31-7.39 (m, 2H), 7.24 (dd,J = 1.8, 7.7 Hz, 1H), 3.57 (d, J = 9.8 Hz, 1H), 2.25 (d, J = 1.9 Hz,3H), 1.21-1.31 (m, 1H), 0.64-0.73 (m, 1H), 0.47-0.60 (m, 2H), 0.38 (ddd,J = 4.6, 9.0, 10.4 Hz, 1H). 9.31 l-bromo-2,5-difluoro-4-(trifluoromethoxy)benzene

(R)-cyclopropyl(2,5-difluoro-4- (trifluoromethoxy)phenyl)methanaminehydrochloride. ¹H NMR (500 MHz, DMSO-d6) δ ppm 8.73 (br s, 3H) 8.03 (dd,J = 10.90, 6.49 Hz, 1H) 7.83 (dd, J = 9.21, 6.62 Hz, 1H) 3.83 (br d, J =9.86 Hz, 1H) 1.35 -1.44 (m, 1H) 0.64-0.74 (m, 2H) 0.51-0.58 (m, 1H) 0.34(dq, J = 9.70, 4.98 Hz, 1H). LCMS-ESI (POS.) m/z: 267.0 (M + H)+.

Intermediate 10.0: Preparation of5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-amine

Step 1: Preparation of (5-iodo-2,3-dihydro-1H-inden-2-yl)carbamate

A 250 mL round-bottom flask was charged with5-iodo-2,3-dihydro-1H-inden-2-amine (5.20 g, 20.0 mmol, Combi-Blocks,Inc.), Boc₂O (4.4 g 20.0 mmol) and 20 mL of DCM. While at rt,1-methylimidazole (2.1 g, 26.1 mmol) was added and the resulting mixturewas allowed to stir at rt for 1 h. The reaction was then concentratedunder reduced pressure and purified by silica gel column chromatography(0-50% EtOAc/heptane) to give tert-butyl(5-iodo-2,3-dihydro-1H-inden-2-yl)carbamate (8.04 g). LCMS-ESI (POS.).m/z: 382.0 (M+Na)+.

Step 2: Preparation of(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)carbamate

A solution of bis(pinacolato)diboron (5.05 g, 19.91 mmol,Sigma-Aldrich), tert-butyl (5-iodo-2,3-dihydro-1H-inden-2-yl)carbamate(6.50 g, 18.10 mmol), PdCl₂(dppf)-CH₂Cl₂ (0.739 g, 0.905 mmol), andpotassium acetate (7.10 g, 72.4 mmol) in 30 mL DMF was heated to 100° C.for 12 h. The reaction mixture was partially concentrated and thenpurified directly by silica gel column chromatography (0-50%EtOAc/heptane) to provide tert-butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)carbamate(6.02 g). LCMS-ESI (POS.). m/z: 382.0 (M+Na)+.

Step 3: Preparation of tert-butyl(5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)carbamate

A solution of tert-butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)carbamate(6.02 g, 16.76 mmol) in 100 mL MeCN and 20 mL DMF was heated to 80° C.in a crystalizing dish. (1,10-phenanthroline)(trifluoromethyl)copper(I)(7.86 g, 25.1 mmol) was added in 1 g portions over one hour. Thereaction mixture was then diluted with saturated aqueous Rochelle® saltand was extracted with DCM. The organics were dried over MgSO₄ andconcentrated. Purification of the crude residue by silica gel columnchromatography (0-50% EtOAc/heptane) gave tert-butyl(5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)carbamate (2.46 g). ¹HNMR (400 MHz, acetonitrile-d₃) δ ppm 7.14-7.55 (m, 3H), 5.47-5.66 (m,1H), 4.31-4.42 (m, 1H), 3.16-3.31 (m, 2H), 2.74-2.92 (m, 2H), 1.41-1.49(m, 9H).

Step 4: Preparation of 5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-amine,Intermediate 10.0

A solution of tert-butyl(5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)carbamate (2.1 g, 7.0mmol) in 10 mL DCM was treated with TFA (5.40 mL, 70.0 mmol) and wasallowed to stir at rt for 12 h. The reaction mixture was concentratedand purified by reverse phase column chromatography (Puriflash C18,10-100% (0.1% NH₄OH in MeOH)/(0.1% NH₄OH in water)] gave5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-amine (0.49 g). LCMS-ESI(POS.). m/z: 202.2 (M+H)+.

Intermediate 11.0: Preparation of tert-butyl3-(amino(4-chloro-2,5-difluorophenyl)methyl)azetidine-1-carboxylate

Step 1: Preparation of tert-butyl3-(4-chloro-2,5-difluorobenzoyl)azetidine-1-carboxylate

Zinc (0.60 g, 9.18 mmol) was added to a 100 mL round-bottom flask andsuspended in THF (20 mL). 1,2-dibromoethane (0.073 mL, 0.848 mmol) wasthen added and the reaction was heated to 65° C. for 5 min and thencooled to rt. Chlorotrimethylsilane (0.090 mL, 0.706 mmol) was added andthe reaction was stirred an additional 30 min at rt and1-boc-3-iodoazetidine (1.23 g, 7.06 mmol) was then added dropwise. After45 min, the reaction was cooled to −10° C., and lithium chloride (0.90g, 21.19 mmol, Sigma-Aldrich) and copper(I) cyanide (0.325 g, 10.60mmol) were introduced. This was stirred for 15 min followed by theaddition of 4-chloro-2,5-difluorobenzoyl chloride (1.20 g, 8.83 mmol).The reaction was then warmed to rt and stirred 1.5 hours. The reactionwas quenched with sat. sodium bicarbonate and extracted with EtOAc,dried with Na₂SO₄, filtered, and concentrated. Purified via columnchromatography (10-20% EtOAc in heptane) to yield the desired product asa white solid (1.6 g). ¹H NMR (500 MHz, chloroform-d) δ ppm 7.76 (br d,J=2.72 Hz, 1H), 7.26 (d, J=5.71 Hz, 1H), 4.15-4.25 (m, 4H), 3.90-4.06(m, 1H), 1.39-1.46 (m, 9H). LCMS-ESI (POS.). m/z: 354.2 (M+Na)+.

Step 2: Preparation of tert-butyl3-(amino(4-chloro-2,5-difluorophenyl)methyl)azetidine-1-carboxylate,Example 11.0

tert-butyl 3-(4-chloro-2,5-difluorobenzoyl)azetidine-1-carboxylate (1.6g, 4.8 mmol) was dissolved in MeOH at rt. Added ammonium acetate (3.47g, 48.2 mmol) followed by sodium cyanoborohydride (0.91 g, 14.5 mmol) inportions. The mixture was then heated at reflux for 1 h and then cooledto rt, concentrated, and then dissolved in saturated aqueous NaHCO₃ andEtOAc. The organics were dried with Na₂SO₄, filtered, and concentratedto colorless oil. Purification via column chromatography (10-100%EtOAc/heptanes) provided the desired product (0.88 g). ¹H NMR (500 MHz,chloroform-d) δ ppm 7.26-7.30 (m, 1H), 7.09-7.18 (m, 1H), 5.06-5.14 (m,1H), 3.84-3.95 (m, 3H), 3.70-3.80 (m, 1H), 2.79-2.93 (m, 1H), 1.38-1.46(m, 9H).

Intermediate 12.0: Preparation of 4-(methylsulfonyl)picolinic Acid

Step 1: Preparation of methyl 4-(methylsulfonyl)picolinate

To a solution of methyl 4-chloropicolinate (5.0 g, 29.1 mmol,Combi-Blocks, Inc.) in NMP (45 mL) were added sodium methanesulfinate(3.72 g, 36.4 mmol, Oakwood Chemical, Inc.), quinoline (0.345 g, 2.91mmol) and copper(II) chloride (0.392 g, 2.91 mmol). The reaction mixturewas stirred at 150° C. for 5 h then allowed to cool to rt and quenchedwith water (50 mL). The reaction mixture was extracted with DCM (3×50mL), washed with water (2×100 mL), and brine (100 mL). The organic layerwas dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude material was purified using silica gel (60-120 mesh)eluting with 55-70% EtOAc/hexanes to give methyl4-(methylsulfonyl)picolinate (2.5 g) as a pale yellow solid. ¹H NMR (400MHz, chloroform-d): δ 9.07 (d, J=4.8 Hz, 1H), 8.62 (s, 1H), 8.02 (d,J=4.8 Hz, 1H), 4.08 (s, 3H), 3.15 (s, 3H). LCMS-ESI (POS.). m/z: 216.1(M+H)+.

Step 2: Preparation of Synthesis of 4-(methylsulfonyl)picolinic Acid,Intermediate 12.0

To a solution of methyl 4-(methylsulfonyl)picolinate (1.0 g, 4.65 mmol)in EtOH (12 mL) was added a solution of 1.5M NaOH in water (12 mL). Thereaction mixture was stirred at rt for 1 h and then concentrated underreduced pressure. The remaining aqueous solution was cooled to 10° C.and acidified to pH 2 using 3N HCl. The precipitated solid was collectedby filtration, washed with water (2×20 mL), and dried under vacuum togive 4-(methylsulfonyl)picolinic acid (0.65 g) as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 13.77 (s, 1H), 9.06 (d, J=5.2 Hz, 1H), 8.42(s, 1H), 8.14 (d, J=5.2 Hz, 1H), 3.41 (s, 3H). LCMS-ESI (NEG). m/z:200.1 (M−H)+.

Intermediate 13.0: Preparation of 3-(N,N-dimethylsulfamoyl)benzoic Acid

Preparation of 3-(N,N-dimethylsulfamoyl)benzoic Acid, Intermediate 13.0

To a round-bottom flask was added dimethylamine (2.0M in THF, 9.1 mL,18.2 mmol) and DCM (40 mL). The solution was cooled to 0° C. and DIPEA(7.88 mL, 45.3 mmol) was added followed by 3-(chlorosulfonyl)benzoicacid (4.0 g, 18.1 mmol) in portions maintaining the temperature <5° C.The reaction was stirred at 0° C. for 2 h then 1N NaOH (50 mL) was addedand the phases were separated. The organics were washed with 1N NaOH(2×50 mL) and the aqueous extracts were collected and acidified withconc. HCl to pH 2. The resulting precipitate was collected by filtrationand dried under reduced pressure to give the desired product (2.93 g).¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.55 (br s, 1H), 8.23-8.29 (m, 1H),8.18-8.22 (m, 1H), 7.95-8.06 (m, 1H), 7.74-7.85 (m, 1H), 2.63 (s, 6H).LCMS-ESI (POS.). m/z: 230.2 (M+H)+.

The compounds set forth in the following table were synthesizedfollowing the procedure described for Intermediate 13.0 using knownstarting material replacements as described.

TABLE 3 Intermediate Reagents Structure, Name and Data 13.13.3-difluoroazetidine hydrochloride (Synthonix, Inc.)

3-((3,3-difluoroazetidin-1-yl)sulfonyl)benzoic acid. LCMS-ESI (POS.).m/z: 278.0 (M + H)+. 13.2 N-isopropylmethylamine (Acros Organics)

3-(N-isopropyl-N-methylsulfamoyl)benzoic acid. LCMS-ESI (POS.). m/z:258.2 (M + H)+. 13.3 Azetidine (Matrix Scientific)

3-(azetidin-1-ylsulfonyl)benzoic acid. LCMS- ESI (POS.). m/z: 242.0 (M +H)+. 13.4 N,O- dimethylhydroxylamine hydrochloride (ACROS Organics)

3-(N-methoxy-N-methylsulfamoyl)benzoic acid. LCMS-ESI (POS.). m/z: 246.0(M + H)+. 13.5 Diethylamine

3-(N,N-diethylsulfamoyl)benzoic acid. LCMS-ESI (POS.). m/z: 258.2 (M +H)+. 13.6 (2,2,2- trifluoroethyl)methylamine (Oakwood Products)

3-(N-methyl-N-(2,2,2-trifluoroethyl)sulfamoyl)benzoic acid. LCMS-ESI(POS). m/z: 298.0 (M + H)+. 13.7 3-hydroxy-3- methylazetidinehydrochloride (Matrix Scientific)

3-((3-hydroxy-3-methylazetidin-1-yl)sulfonyI)benzoic acid. ¹H NMR (400MHz. DMSO-d₆) δ 13.58 (br s, 1H), 8.30 (td, J = 1.31, 7.85 Hz, 1H), 8.24(t, J = 1.55 Hz, 1H), 8.00-8.10 (m, 1H), 7.84 (t, J = 7.77 Hz, 1H), 5.61(br s, 1H), 3.60 (d, J = 8.50 Hz, 2H), 3.46 (d, J = 8.19 Hz, 2H), 1.21(s, 3H). 13.8 2-(chlorosulfonyl) isonicotinic acid hydrochloride(Astatech) 3-cyano-azetidine hydrochloride (Advanced Chem Blocks)

2-((3-cyanoazetidin-1-yl)sulfonyl)isonicotinic acid. LCMS-ESI (POS.).m/z: 268.0 (M + H)+. 13.9 2-oxo-6-azaspiro[3.3]- heptane (JW Pharma Lab)

3-(2-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl) benzoic acid. LCMS-ESI(POS.). m/z: 284.2 (M + H)+. 13.10 3-methoxyazetidine hydrochloride (JWPharma Lab)

3-((3-methoxyazetidin-1-yl)sulfonyl)benzoic acid. LCMS-ESI (POS.). m/z:272.2 (M + H)+.

Intermediate 14.0: Preparation of 3-(N,N-dimethylsulfamoyl)benzoic Acid

Step 1: Preparation of benzyl(3-(N,N-dimethylsulfamoyl)benzoyl)-D-prolinate

To a 250 mL round-bottom flask was added3-(N,N-dimethylsulfamoyl)benzoic acid (1.8 g, 7.9 mmol), TBTU (2.5 g,7.9 mmol), (R)-benzyl pyrrolidine-2-carboxylate hydrochloride (1.9 g,7.9 mmol) and dichloromethane (40 mL). After cooling to 0° C., DIPEA(4.1 mL, 23.6 mmol) was added. The reaction was allowed to warm to 23°C. and stirred for an additional 5 h then 1N HCl (20 mL) was added. Theorganics were separated and concentrated under reduced pressure and thecrude residue was purified using silica gel chromatography (50-100%EtOAc/heptanes) to obtain the desired product as a vicious oil. LCMS-ESI(POS.). m/z: 417.2 (M+H)+.

Step 2: Preparation of (3-(N,N-dimethylsulfamoyl)benzoyl)-D-proline,Intermediate 14.0

To a pressure vessel was added(3-(N,N-dimethylsulfamoyl)benzoyl)-D-prolinate (3.27 g, 7.85 mmol) andmethanol (40 mL). The solution was sparged and backfilled with nitrogen.10% Pd/C (0.084 g, 0.785 mmol) was carefully added and the vessel wascharged with hydrogen (40 psi) and stirred for 12 h at rt. The solutionwas filtered through Celite and concentrated to give the crude product.Purification using silica gel column chromatography (0-10% MeOH:DCM)provided the desired product as a vicious oil (2.27 g). LCMS-ESI (POS.).m/z: 327.0 (M+H)+.

Intermediate 15.0: Preparation of(rac)-1-(amino(2-fluoro-4-(trifluoromethyl)phenyl)methyl)cyclopropan-1-olhydrochloride

Step 1: Preparation of ethyl(rac)-2-amino-2-(2-fluoro-4-(trifluoromethyl)phenyl)acetate

A 250 mL round-bottom flask was charged with2-amino-2-(2-fluoro-4-(trifluoromethyl)phenyl)acetic acid (22.1 g, 93mmol) and ethanol (200 mL). To that solution was added thionyl chloride(20.4 mL, 280 mmol). The flask was fitted with a reflux condenser andheated to reflux. After 3 hours, the mixture was cooled and thevolatiles were concentrated under reduced pressure. The oil wasazeotroped with ethanol (50 mL×3). The crude material was diluted withethyl acetate (˜150 mL) and 6N HCl (200 mL) and stirred for 30 minutesthen transferred into a separatory funnel. The organics were extractedwith water (150 mL×5). The pH of the water was adjusted to ˜8 using 6Nsodium hydroxide and then extracted with chloroform (50 mL×5) to give(rac)-2-amino-2-(2-fluoro-4-(trifluoromethyl)phenyl)acetate (7.28 g,27.5 mmol) as an off-white solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.74(br t, J=7.46 Hz, 1H) 7.54-7.69 (m, 2H) 4.80 (s, 1H) 4.05-4.15 (m, 2H)2.40 (br s, 2H) 1.12 (t, J=7.01 Hz, 3H). LCMS-ESI (POS.). m/z: 266.2(M+H)+.

Step 2: Preparation of ethyl(rac)-2-(dibenzylamino)-2-(2-fluoro-4-(trifluoromethyl)phenyl)acetate

A 100 mL round-bottom flask was charged with(rac)-2-amino-2-(2-fluoro-4-(trifluoromethyl)phenyl)acetate (7.3 g, 27.5mmol) and suspended in acetonitrile (70 mL). To that suspension wasadded DIPEA (19.2 mL, 110 mmol) followed by (bromomethyl)benzene (13.1mL, 110 mmol). The flask was fitted with a condenser and heated toreflux. After 21 hours, the contents of the flask were concentratedunder reduced pressure and the resulting solids were dissolved with DCMand purified by silica gel chromatography eluting with 0-10% ethylacetate/heptane to provide the desired product (10.98 g) as a paleyellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.56-7.82 (m, 3H) 7.19-7.43(m, 10H) 3.26-4.26 (m, 7H) 1.11-1.30 (m, 3H). LCMS-ESI (POS.). m/z:446.0 (M+H)+.

Step 3: Preparation of(rac)-1-((dibenzylamino)(2-fluoro-4-(trifluoromethyl)phenyl)methyl)cyclopropan-1-ol

A 250 mL round-bottom flask was charged with ethyl(rac)-2-(dibenzylamino)-2-(2-fluoro-4-(trifluoromethyl)phenyl)acetate(11 g, 24.7 mmol) and diluted with THF (82 mL). While at rt,titanium(IV) isopropoxide (3.7 mL, 12.3 mmol) was added. Ethylmagnesiumbromide 3.0M in diethyl ether (30.0 mL, 90 mmol) was then added dropwisevia syringe pump over the course of 1.75 hours. Immediately afteraddition was complete, the reaction mixture was quenched with asaturated solution of NH₄Cl. After stirring at rt for an additional 30minutes, the mixture was filtered through a pad of Celite, transferredto a separatory funnel, and diluted with ethyl acetate (250 mL). Thelayers were separated and the aqueous was extracted with ethyl acetate(50 mL×3). The combined organic extracts were dried with magnesiumsulfate, filtered, concentrated under reduced pressure and purified bysilica gel chromatography eluting with 0-10% ethyl acetate/heptane togive the desired product (6.96 g) as a viscous, pale yellow oil. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 8.19 (br t, J=7.46 Hz, 1H) 7.58-7.66 (m, 2H)7.25-7.35 (m, 8H) 7.17-7.24 (m, 2H) 5.46 (s, 1H) 3.93 (br d, J=14.14 Hz,2H) 3.67 (br d, J=14.14 Hz, 2H) 3.57 (s, 1H) 0.84-0.93 (m, 1H) 0.52-0.60(m, 1H) 0.40-0.51 (m, 1H) 0.22-0.33 (m, 1H). LCMS-ESI (POS.). m/z: 430.0(M+H)+.

Step 4: Preparation of(rac)-1-(amino(2-fluoro-4-(trifluoromethyl)phenyl)methyl)cyclopropan-1-olIntermediate, 15.0

A 125 mL pressure flask was charged with 10% Pd/C (0.077 g, 0.871 mmol)under an atmosphere of nitrogen. Ethanol (50 mL) was added followed by(rac)-1-((dibenzylamino)(2-fluoro-4-(trifluoromethyl)phenyl)methyl)cyclopropan-1-ol(3.74 g, 8.71 mmol). The flask was sealed charged with 25-35 psi withhydrogen. After 1 hour, Celite was added and the slurry was filtered.The filter cake was washed with ethanol (25 mL×5) to give 1.99 g ofdesired product as a dark green solid. The solids were then dissolved in5 mL ethyl acetate and 4.0M HCl in dioxane (10 mL) stirred for 15minutes at rt. The mixture was concentrated and triturated with ethylacetate to give(rac)-1-(amino(2-fluoro-4-(trifluoromethyl)phenyl)methyl)cyclopropan-1-ol(1 g) as a gray solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.68 (br s, 3H)7.91 (t, J=7.59 Hz, 1H) 7.72-7.85 (m, 2H) 6.01 (s, 1H) 4.27 (s, 1H)0.79-0.95 (m, 2H) 0.62-0.76 (m, 2H). LCMS-ESI (POS.). m/z: 250.2 (M+H)+.

The compounds set forth in the following table were synthesizedfollowing the procedure described for Intermediate 15.0 using knownstarting material replacements as described.

TABLE 4 Intermediate Reagents Structure, Name and Data 15.1 methyl2-amino-2-(4- chloro-2,5- difluorophenyl)acetate (AP Bioscience)

1-(amino(4-chloro-2,5- difluorophenyl)methyl)cyclo- propanol LCMS-ESI(POS.) m/z: 234.1 (M + H)⁺.

Intermediate 16.0: Preparation of 3-(2-hydroxypropan-2-yl)benzoic Acid

Step 1: Preparation of 3-(2-hydroxypropan-2-yl)benzoic Acid,Intermediate 16.0

3-acetylbenzoic acid (5 g, 30.5 mmol) was suspended in THF (150 mL) andcooled to −78° C. 3.4M methylmagnesium bromide solution in 2-MeTHF (22.4mL, 76 mmol) was added dropwise over 15 min and then stirred at −78° C.for an additional 3 h. The reaction was then quenched with 1M HCl (20mL) and extracted with EtOAc (2×100 mL). The organics were dried usingNa₂SO₄, filtered, and concentrated to deliver the desired product. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 12.71-13.04 (m, 1H), 8.03-8.13 (m, 1H),7.73-7.80 (m, 1H), 7.66-7.73 (m, 1H), 7.39-7.49 (m, 1H), 5.08-5.19 (m,1H), 1.37-1.48 (m, 6H).

Intermediate 17.1: Preparation of3-(2,2,2-trifluoro-1-hydroxyethyl)benzoic Acid

Step 1: Preparation of methyl 3-(2,2,2-trifluoro-1-hydroxyethyl)benzoate

A 100 mL round-bottom flask was charged with methyl 3-formylbenzoate(3.28 g, 20.0 mmol), (trifluoromethyl)trimethylsilane, (2.0M in THF,15.0 mL, 30.0 mmol) in THF (40.0 mL). The reaction was cooled to 0° C.and then TBAF (1.0M solution in THF, 0.50 mL, 0.50 mmol) was added. Themixture was allowed to warm to rt and after stirring for 1 hour at thattemperature another 4.0 mL of 1M TBAF in THF was added. The mixture wasthen concentrated, diluted with ethyl acetate, then washed withsaturated aqueous NaHCO₃, water, brine. The organics were dried overNa₂SO₄, filtered, and concentrated to give a brown gum. The crudeproduct was purified by silica gel chromatography (5-30% ethylacetate/heptane) to give methyl3-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (3.69 g) as a white solid. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 8.12 (s, 1H), 7.98 (dd, J=7.78, 1.30 Hz,1H), 7.77 (br d, J=7.79 Hz, 1H), 7.58 (t, J=7.79 Hz, 1H), 7.00 (d,J=5.45 Hz, 1H), 5.30-5.36 (m, 1H). LCMS-ESI (POS.) m/z: 235.2 (M+H)+.

Step 2: Preparation of 3-(2,2,2-trifluoro-1-hydroxyethyl)benzoic Acid,Intermediate 17.1

A 25 mL round-bottom flask was charged with methyl3-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (500 mg, 2.14 mmol), 2Mlithium hydroxide in water (1.60 mL, 3.20 mmol) in THF (8.5 mL). Thereaction was stirred at 23° C. for 18 hours. The reaction wasconcentrated to give a white solid and used without furtherpurification. LCMS-ESI (POS.) m/z: 221.2 (M+H)+.

The compounds set forth in the following table were synthesizedfollowing the procedure described for Intermediate 17.1 using knownstarting material replacements as described.

TABLE 5 Intermediate Reagents Structure, Name and Data 17.0 methyl 3-acetylbenzoate (Accela)

3-(1,1,1-trifluoro-2-hydroxypropan- 2-yl)benzoic acid LCMS-ESI (POS.)m/z: 235.2 (M + H)⁺.

Intermediate 18.0: Preparation of3-((2-methoxy-2-oxoethyl)sulfonyl)benzoic Acid

Step 1: Preparation of 3-((2-methoxy-2-oxoethyl)thio)benzoic Acid

A 50 mL round-bottom flask with was charged with anhydrous potassiumcarbonate (610 mg, 4.41 mmol), 3-mercaptobenzoic acid (340 mg, 2.205mmol, TCl America), chloroacetic acid methyl ester (193 μL, 2.21 mmol)and acetonitrile (4.4 mL). The reaction was stirred at rt for 2 h thendiluted with water (10 mL). The pH was adjusted to 1 using 6N HCl andthen extracted with DCM (3×25 mL). The combined organics were washedwith brine, passed through phase separation filter, and concentrated togive a white solid that was used without further purification. LCMS-ESI(POS.) m/z: 249.0 (M+Na)+.

Step 2: Preparation of 3-((2-methoxy-2-oxoethyl)sulfonyl)benzoic Acid,Intermediate 18.0

A 50 mL round-bottom flask was charged with3-((2-methoxy-2-oxoethyl)thio)benzoic acid (450 mg, 2.0 mmol), MCPBA(936 mg, 4.2 mmol) in DCM (8.0 mL). The reaction was then stirred at 23°C. for 2 hours, concentrated, and purified by silica gel chromatography(0-5% 10:1 AcOH:MeOH in DCM) to afford the desired product as a whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 13.42-13.74 (m, 1H), 8.37-8.46(m, 1H), 8.26-8.35 (m, 1H), 8.11-8.22 (m, 1H), 7.71-7.87 (m, 1H),4.71-4.84 (m, 2H), 3.51-3.65 (m, 3H).

Intermediate 19.0: 4-bromo-2,5-difluorobenzaldehyde

Step 1: Preparation of 4-bromo-2,5-difluorobenzaldehyde, Intermediate19.0

A 250 mL round-bottom flask was charged with4-bromo-2,5-difluorobenzaldehyde (5.0 g, 22.6 mmol), triethylaminetrihydrofluoride (7.44 mL, 45.2 mmol) and DCM (45.2 mL). The solutionwas cooled to 0° C. followed by addition of(diethylamino)difluorosulfonium tetrafluoroborate (Xtalfluor-E®, 10.4 g,45.2 mmol). The reaction was stirred for 1 h at 0° C. and then allowedto warm to rt and stirred for an additional 2 h. The solution was thencooled to 0° C. followed by dropwise addition of 1N NaOH until pH 7. Themixture was diluted with DCM, the layers were separated, the organicswere passed through a phase separation column, and then concentrated togive a brown oil. ¹H NMR (500 MHz, chloroform-d) δ ppm 7.32-7.45 (m,2H), 6.68-6.98 (m, 1H).

Intermediate 20.0: 3-((3-(Methoxycarbonyl)cyclobutyl)thio)benzoic Acid

Step 1: Preparation of 3-((3-(Methoxycarbonyl)cyclobutyl)thio)benzoicacid, Intermediate 20.0

A mixture of 3-mercaptobenzoic acid (2.1 g, 13.5 mmol), methyl3-chlorocyclobutanecarboxylate (4.0 g, 26.9 mmol; purchased as a 9:1diastereomeric mixture (favoring trans) from Synthonix, Inc.), andpotassium carbonate (7.43 g, 53.8 mmol) in DMF was stirred at 50° C. for16 h. The reaction mixture was diluted with water and extracted withEtOAc. The combined organic layers were washed with brine, dried overMgSO₄, and concentrated under reduced pressure. The crude material waspurified by MPLC using silica gel and eluting with a 0-40% EtOAc/EtOH(3:1) in heptane to provide3-((3-(methoxycarbonyl)cyclobutyl)thio)benzoic acid (2.02 g) as whitepowder. ¹H NMR (400 MHz, DMSO-d₆) δ 12.91-13.22 (m, 1H), 7.74-7.77 (m,2H), 7.44-7.49 (m, 2H), 3.96 (tt, J=7.77, 8.97 Hz, 1H), 3.56-3.61 (m,3H), 3.11-3.23 (m, 1H), 2.67-2.73 (m, 2H), 2.10-2.21 (m, 2H). LCMS-ESI(POS.) m/z: 289.0 (M+Na)+.

Intermediate 21.0: 4-(4-(trifluoromethyl)benzoyl)pyrrolidin-2-one

Step 1: Preparation of N-methoxy-N-methyl-5-oxopyrrolidine-3-carboxamide

A solution of 5-oxopyrrolidine-3-carboxylic acid (1.0 g, 7.8 mmol),DIPEA (2.71 mL, 15.49 mmol) and N,O-dimethylhydroxylamine hydrochloride(0.755 g, 7.75 mmol) in DCM (20 mL) was cooled to 0° C. EDChydrochloride (1.6 g, 8.5 mmol) was added and the reaction mixture wasallowed to warm to rt and stir for additional 3 h. The mixture wasdiluted with saturated NaHCO₃ solution and the aqueous layer wasextracted DCM (25 mL, 5×). The combined organic layers were dried overMgSO₄, filtered, and concentrated under reduced pressure. The crudematerial was purified by MPLC using silica gel eluting with a gradientof 10-100% EtOAc/EtOH (3:1) in heptane to provideN-methoxy-N-methyl-5-oxopyrrolidine-3-carboxamide (0.88 g) as colorlessoil. ¹H NMR (400 MHz, chloroform-d) δ 6.08-6.25 (m, 1H), 3.65-3.77 (m,4H), 3.56-3.63 (m, 2H), 2.64-2.79 (m, 1H), 2.52 (dd, J=9.48, 16.95 Hz,1H).

Step 2: Preparation of 4-(4-(trifluoromethyl)benzoyl)pyrrolidin-2-one

N-methoxy-N-methyl-5-oxopyrrolidine-3-carboxamide (0.27 g, 1.57 mmol)and 1-bromo-4-(trifluoromethyl)benzene (0.98 g, 4.39 mmol) weredissolved in THF (6.3 mL) and cooled to −78° C. A solution of n-BuLi(1.6M in hexanes, 1.69 mL, 4.23 mmol) was added dropwise and thereaction mixture was stirred at −78° C. for an additional 20 min. Thereaction was diluted with EtOAc and quenched with saturated aqueousNH₄Cl solution and diluted with EtOAc. The organics were separated,dried over MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was suspended in heptane and filtered to give4-(4-(trifluoromethyl)benzoyl)pyrrolidin-2-one (0.20 g) as white solid.LCMS-ESI (POS.) m/z: 258.0 (M+H)+.

Step 3: Preparation of4-(amino(4-(trifluoromethyl)phenyl)methyl)pyrrolidin-2-one, Intermediate21.0

A solution of 4-(4-(trifluoromethyl)benzoyl)pyrrolidin-2-one (0.2 g,0.78 mmol) in methanol (7.8 mL) was treated with ammonium acetate (0.6g, 7.8 mmol) and sodium cyanoborohydride (0.147 g, 2.3 mmol). Thereaction mixture was stirred at rt for 16 h and then concentrated andpartitioned between DCM and a saturated aqueous NaHCO₃. The aqueouslayer was extracted with DCM, and the combined organic extracts weredried over MgSO₄, filtered, and concentrate to afford crude4-(amino(4-(trifluoromethyl)phenyl)methyl)pyrrolidin-2-one as lightyellow oil. This product was directly used in the subsequent reactionwithout further purification. LCMS-ESI (POS.) m/z: 259.0 (M+H)+.

The compounds set forth in the following table were synthesizedfollowing the procedure described for Intermediate 21.0 using knownstarting material replacements as described.

TABLE 6 Intermediate Reagents Structure, Name and Data 21.1 1-bromo-2-fluoro-4- (trifluoro- methyl)- benzene (Combi- Blocks, Inc)

4-(amino(2-fluoro-4- (trifluoromethyl)phenyl)methyl)pyrrolidin- 2-oneLCMS-ESI (POS.) m/z: 291.0 (M + H)+ 21.2 1-bromo-2,5- difluoro-4-(trifluoro- methyl) benzene (Combi- Blocks)

4-(amino(2,5-difluoro-4- (trifluoromethyl)phenyl)methyl)pyrrolidin-2-one LCMS-ESI (POS.) m/z: 295.1 (M + H)+

Intermediate22.0:4-(2-Fluoro-4-(trifluoromethyl)benzoyl)pyrrolidin-2-one

Step 1: Preparation ofN-Methoxy-N,1-dimethyl-5-oxopyrrolidine-3-carboxamide

This compound was prepared from 1-methyl-5-oxopyrrolidine-3-carboxylicacid (1.00 g, 6.99 mmol) in the same manner as the one described in thepreparation of 21.0. ¹H NMR (500 MHz, DMSO-d₆) δ 3.66-3.72 (m, 3H),3.52-3.59 (m, 2H), 3.34-3.38 (m, 1H), 2.68-2.73 (m, 3H), 2.41-2.46 (m,2H).

Step 2: Preparation of4-(2-Fluoro-4-(trifluoromethyl)benzoyl)-1-methylpyrrolidin-2-one

This compound was prepared fromN-methoxy-N,1-dimethyl-5-oxopyrrolidine-3-carboxamide (0.98 g, 5.26mmol) and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (1.79 g, 7.37mmol) in the same manner as the one described in the preparation of21.0, except that the crude product was purified by MPLC using silicagel eluting with a gradient of 0-35% mixed EtOAc/EtOH (3:1) in heptane.LCMS-ESI (POS.) m/z: 290.2 (M+H)+.

Step 3: Preparation of4-(amino(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-methylpyrrolidin-2-one,Intermediate 22.0

A mixture of4-(2-fluoro-4-(trifluoromethyl)benzoyl)-1-methylpyrrolidin-2-one (0.21g, 0.73 mmol), potassium acetate (0.106 g, 1.70 mmol) and hydroxylaminehydrochloride (0.065 g, 1.55 mmol) in DCM (4 mL) was stirred at 50° C.for 12 h. The mixture was diluted with EtOAc and washed with water. Theaqueous fractions were extracted with EtOAc, and the combined organiclayers were dried over MgSO₄, filtered, and concentrated under reducedpressure to provide crude oxime product4-((2-fluoro-4-(trifluoromethyl)phenyl)(hydroxyimino)methyl)-1-methylpyrrolidin-2-one(0.20 g). LCMS-ESI (POS.) m/z: 305.0 (M+H)+. This product was directlyused in the subsequent reaction without further purification.

To a 25-mL pressure flask was added a solution of4-((2-fluoro-4-(trifluoromethyl)phenyl)(hydroxyimino)methyl)-1-methylpyrrolidin-2-one(0.20 g, 0.657 mmol) in AcOH (3 mL). Zinc dust (420 mg, 6.57 mmol) wasadded and the reaction mixture stirred at 50° C. for 12 h. The remainingsolid was filtered off, the filtrate was concentrated, dissolved in DCM,and treated with a saturated aqueous NaHCO₃. The biphasic mixture wasstirred for 10 min then extracted with DCM. The combined organic layerswere dried over MgSO₄, filtered, and concentrated to afford crude4-(amino(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-methylpyrrolidin-2-oneas yellow oil. This product was directly used in the subsequentreactions without further purification. LCMS-ESI (POS.) m/z: 291.2(M+H)+.

Intermediate 23.0:(R)-1-(3-(methylthio)benzoyl)-2,3-dihydro-1H-pyrrole-2-carboxylic Acid

Step 1: Preparation of (R)-Ethyl1-(3-(methylthio)benzoyl)-5-oxopyrrolidine-2-carboxylate

To a 25-mL vial was added 3-(methylthio)benzoic acid (0.3 g, 1.78 mmol),DCM (3.5 mL) and a few drops of DMF. Oxalyl chloride (0.19 mL, 2.14mmol) was added dropwise, and the reaction mixture was stirred at rt for2 h. The solvent was evaporated to afford crude acid chloride product asyellow solid which was directly used in the subsequent reaction withoutpurification.

To a 25-mL vial was added (R)-ethyl 5-oxopyrrolidine-2-carboxylate (0.18g, 1.13 mmol), DIPEA (0.586 mL, 4.53 mmol), DMAP (0.028 g, 0.227 mmol),and DCM (4.25 mL). The acid chloride from above (0.317 g, 1.7 mmol) wasadded in several portions over 5 min, and the resulting reaction mixturewas stirred at rt for 12 h. The reaction was quenched with a saturatedaqueous NaHCO₃, and the aqueous fraction was extracted with DCM. Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated under reduced pressure. The crude material was purified byMPLC using silica gel and eluting with 0-30% EtOAc in heptane to provide(R)-ethyl 1-(3-(methylthio)benzoyl)-5-oxopyrrolidine-2-carboxylate (0.34g) as colorless oil. LCMS-ESI (POS.) m/z: 308.2 (M+H)+. ¹H NMR (400 MHz,chloroform-d) δ 7.50-7.58 (m, 1H), 7.38-7.46 (m, 2H), 7.30-7.38 (m, 1H),4.89 (dd, J=3.89, 8.86 Hz, 1H), 4.28 (dq, J=0.98, 7.14 Hz, 2H),2.69-2.85 (m, 1H), 2.55-2.65 (m, 1H), 2.42-2.54 (m, 4H), 2.18 (dq,J=4.15, 8.91 Hz, 1H), 1.32 (t, J=7.10 Hz, 3H).

Step 2: Preparation of(R)-1-(3-(methylthio)benzoyl)-2,3-dihydro-1H-pyrrole-2-carboxylic Acid,Intermediate 23.0

A solution of (R)-ethyl1-(3-(methylthio)benzoyl)-5-oxopyrrolidine-2-carboxylate (0.35 g, 1.14mmol) in toluene (7.6 mL) was cooled to −78° C. and treated withLi(Et)₃BH (1M in THF, 1.25 mL, 1.25 mmol) dropwise. After 30 min at −78°C., DIPEA (1.03 mL, 7.97 mmol) and DMAP (0.014 g, 0.11 mmol) were added,followed by dropwise addition of TFAA (0.178 mL, 1.25 mmol). Thereaction mixture was allowed to slowly warm to rt and stir for anadditional 3 h. The reaction was concentrated and the crude material waspurified by MPLC using silica gel and eluting with 0-30% EtOAc inheptane to provide (R)-ethyl1-(3-(methylthio)benzoyl)-2,3-dihydro-1H-pyrrole-2-carboxylate (0.087 g)as yellow oil. LCMS-ESI (POS.) m/z: 292.2 (M+H)+. ¹H NMR (400 MHz,chloroform-d) δ 7.32-7.46 (m, 4H), 6.52 (br s, 1H), 5.14 (br s, 1H),5.01 (dd, J=4.87, 11.40 Hz, 1H), 4.26-4.33 (m, 2H), 3.06-3.21 (m, 1H),2.69-2.81 (m, 1H), 2.51-2.52 (m, 3H), 1.30-1.36 (m, 3H).

(R)-ethyl 1-(3-(methylthio)benzoyl)-2,3-dihydro-1H-pyrrole-2-carboxylate(0.08 g, 0.275 mmol) was dissolved in 1,4-dioxane (1.4 mL) and treatedwith lithium hydroxide (0.032 g, 1.373 mmol). The solution was stirredat rt for 3 h and then diluted with water and acidified with 1N HCl topH=3. The mixture was extracted with EtOAc, and the combined organiclayers were dried over MgSO₄, filtered, and concentrated under reducedpressure to afford crude(R)-1-(3-(methylthio)benzoyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acidas light-yellow oil. This material was directly used in subsequentreactions without further purification. LCMS-ESI (POS.) m/z: 264.2(M+H)+.

Intermediate 24.0:(S)-3-((R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-sulfonylchloride

Step 1: Preparation of (S)-tert-butyl3-((R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-carboxylate

To a solution of (S)-1-Boc-piperidine-3-carboxylic acid (93 mg, 0.404mmol) and TBTU (142 mg, 0.441 mmol) in DCM (15.7 mL) is added DIPEA(0.23 mL, 1.29 mmol). The reaction mixture was stirred for 5 min andthen treated with(R)—N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide (100 mg,0.367 mmol) as a solution in DCM (2 mL). After 1 h, the solvent wasevaporated, and the mixture was purified by MPLC using silica geleluting with a gradient of 5-40% mixed EtOAc/EtOH (3:1) in heptane toprovide (S)-tert-butyl 3-((R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-carboxylate (148 mg). ¹H NMR (500MHz, DMSO-d₆) (8.29-8.79 (m, 1H), 7.60-7.77 (m, 2H), 7.36-7.57 (m, 2H),4.23-4.51 (m, 3H), 3.81-4.08 (m, 2H), 3.42-3.73 (m, 2H), 3.27-3.38 (m,1H), 2.05-2.25 (m, 1H), 1.71-2.01 (m, 4H), 1.43-1.68 (m, 2H), 1.31-1.42(m, 10H).

Step 2: Preparation of(S)-3-((R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-sulfonylchloride, Intermediate 24.0

(S)-tert-butyl3-((R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-carboxylate(4.48 g, 9.27 mmol) was dissolved in DCM (50 mL). TFA (25 mL) was addedslowly, and the reaction mixture was stirred at rt for 1 h. The reactionwas concentrated and the residue was dissolved in DCM and washed with 2NNaOH. The organic layers were dried over MgSO₄, filtered, andconcentrated under reduced pressure to provide crude(R)-1-((S)-piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide(3.55 g). LCMS-ESI (POS.) m/z: 384.2 (M+H)+. 2.74 g (7.15 mmol) of thisproduct was dissolved in DCM (84.0 mL) and cooled to −30° C. To thissolution was added DIPEA (2.49 mL, 14.30 mmol) and sulfuryl chloride(1.74 mL, 21.5 mmol). The reaction mixture was allowed to warm to rt andstirred for an additional 1 h. The reaction was concentrated and themixture was purified by MPLC using silica gel eluting 5-50% EtOAc/EtOH(3:1) in heptane to provide(S)-3-((R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-sulfonylchloride (2.88 g). ¹H NMR (500 MHz, chloroform-d) δ 7.58 (d, J=8.17 Hz,2H), 7.37 (br d, J=8.04 Hz, 3H), 4.61 (dd, J=2.21, 8.04 Hz, 1H),4.49-4.57 (m, 1H), 4.38-4.47 (m, 1H), 3.92 (br dd, J=1.88, 12.00 Hz,2H), 3.45-3.70 (m, 2H), 3.03 (t, J=11.68 Hz, 1H), 2.82-2.89 (m, 1H),2.76-2.81 (m, 1H), 2.44 (qdd, J=3.00, 6.34, 9.33 Hz, 1H), 2.14-2.30 (m,1H), 2.01-2.11 (m, 1H), 1.89-1.99 (m, 3H), 1.74-1.86 (m, 1H), 1.44-1.57(m, 1H).

The compounds set forth in the following table were synthesizedfollowing the procedure described for Intermediate 24.0 using knownstarting material replacements as described.

TABLE 7 Intermediate Reagents Structure, Name and Data 24.1 2-fluoro-4-(trifluoro- methyl)- benzylamine (Enamine, Ltd.).

(S)-3-((R)-2-((2-fluoro-4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-sulfonyl chloride. ¹H NMR(400 MHz, chloroform-d) δ ppm 7.29-7.49 (m, 4H), 4.39-4.67 (m, 3H),3.85-4.00 (m, 2H), 3.50-3.73 (m, 2H), 2.98-3.12 (m, 1H), 2.83-2.90 (m,1H), 2.12-2.48 (m, 2H), 1.74-2.10 (m, 5H), 1.48- 1.62 (m, 1H). 24.2(2R,4S)-1- (tert-butoxy- carbonyl)-4- fluoro- pyrrolidine- 2-carboxylicacid (Synthonix)

(S)-3-((2R,4S)-4-fluoro-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-sulfonyl chloride. LCMS-ESI (POS.) m/z: 402.2 (M + H)+ (penultimateamine)

Intermediate 25.0: 1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylicAcid

Step 1: Preparation of methyl1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate

To a solution of methyl 1H-pyrazole-4-carboxylate (0.3 g, 2.4 mmol) andDBU (0.39 mL, 2.6 mmol) in acetonitrile (12 mL) was slowly addeddimethylsulfamoyl chloride (0.27 mL, 2.51 mmol). The reaction mixturewas stirred at rt for 1 h and was then concentrated under reducedpressure. The resulting residue was partitioned between water and ethylacetate. The organic phase was washed with 10% citric acid, water, andbrine. The organic phase was dried over MgSO₄, filtered, concentratedand purified by silica gel chromatography eluting with a gradient of 5%ethyl acetate in DCM, to provide methyl1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate (0.54 g), LCMS-ESI(POS.) m/z 310.0 (M+H)⁺.

Step 2: Preparation of1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid, Intermediate25.0

To a solution of methyl1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate (0.54 g, 2.32 mmol)in a mixture of 1:1 THF/MeOH (5 mL) was added lithium hydroxide (0.285g, 11.89 mmol) in water (10 mL). The reaction mixture was stirred at rtfor 5 h and was then acidified with to pH=1 with 1N HCl. The solvent wasconcentrated under reduced pressure and the remaining aqueous phase wasextracted with DCM/MeOH (10:1). The combined organic phase was driedover MgSO₄, filtered, and concentrated. The crude was used withoutfurther purification, LCMS-ESI (POS.) m/z 220.0 (M+H)+.

Intermediate 26.0:(2R)-1-(tert-butoxycarbonyl)-4-(difluoromethyl)pyrrolidine-2-carboxylicAcid

Step 1: Preparation of (R)-1-tert-butyl 2-methyl4-(difluoromethylene)pyrrolidine-1,2-dicarboxylate

A solution of 1-tert-butyl 2-methyl(2R)-4-oxopyrrolidine-1,2-dicarboxylate (1.0 g, 3.99 mmol, Synthonix) inTHF (40 mL) was cooled to 0° C. and then treated successively with HMPT(3.18 mL, 16.95 mmol) and dibromodifluoromethane (1.64 mL, 16.95 mmol).The mixture was then removed from the ice bath and allowed to stir at rtfor 1 h. To the mixture was then added zinc dust (1.11 g, 17.0 mmol)followed by HMPT (0.19 mL, 1.04 mmol) and then heated at reflux for 3.5h. The mixture was then cooled to rt, diluted with water and EtOAc, andthen filtered through Celite washing with EtOAc. The organics wereseparated and the aqueous was extracted with EtOAc (2×). The combinedorganics were then washed with saturated aqueous CuSO₄ (1×), water (1×),brine (1×), and then dried over Na₂SO₄ and concentrated to afford 510 mgof a brown oil. The crude was purified via flash chromatography (0-10%EtOAc in heptanes) to afford 292 mg of 1-(tert-butyl) 2-methyl(R)-4-(difluoromethylene)pyrrolidine-1,2-dicarboxylate as a clear,colorless oil. ¹H NMR (400 MHz, chloroform-d) δ ppm 4.40-4.60 (m, 1H),4.02-4.20 (m, 2H), 3.76 (s, 3H), 2.83-3.02 (m, 1H), 2.67 (br d, J=15.13Hz, 1H), 1.41-1.53 (m, 9H).

Step 2: Preparation of (2R)-1-tert-butyl 2-methyl4-(difluoromethyl)pyrrolidine-1,2-dicarboxylate

To a solution of (R)-1-tert-butyl 2-methyl4-(difluoromethylene)pyrrolidine-1,2-dicarboxylate (280 mg, 1.01) inethanol (10 mL) was added 10% Pd/C (105 mg, 0.987 mmol) and then placedunder an atmosphere of H₂ (30 psi) for 24 h. The mixture was thenfiltered through a Celite washing with ethanol. The filtrate wasconcentrated under reduced pressure to afford 270.2 mg of(2R)-1-tert-butyl 2-methyl4-(difluoromethyl)pyrrolidine-1,2-dicarboxylate as a clear colorlessoil, (5:1 diastereomeric mixture). This mixture was carried forward intonext step without further purification. 1H NMR (500 MHz, chloroform-d) δppm 5.63-5.97 (m, 1H), 4.14-4.54 (m, 1H), 3.65-3.82 (m, 4H), 3.45-3.54(m, 1H), 2.60-2.78 (m, 1H), 2.38-2.54 (m, 1H), 1.93-2.19 (m, 1H),1.37-1.52 (m, 9H).

Step 3: Preparation of(2R)-1-(tert-butoxycarbonyl)-4-(difluoromethyl)pyrrolidine-2-carboxylicacid, Intermediate 26.0

To a solution of (2R)-1-tert-butyl 2-methyl4-(difluoromethyl)pyrrolidine-1,2-dicarboxylate (270 mg, 0.967 mmol) inTHF (2.5 mL) and water (1.25 mL) was added LiOH*hydrate (122 mg, 2.90mmol). The mixture was stirred at rt for 18 h and then concentratedunder reduced pressure to remove the THF. The pH of the remainingaqueous solution adjusted to pH 1-2 with addition of 1N HCl, thenextracted with DCM (3×). The combined organics were dried over Na₂SO₄and concentrated under reduced pressure to afford 269 mg of(2R)-1-(tert-butoxycarbonyl)-4-(difluoromethyl)pyrrolidine-2-carboxylicacid as a white solid. (5:1 diastereomeric mixture). This material wasused without further purification.

Intermediate 27.0:(R)-1-((S)-piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamidehydrochloride

Step 1: Preparation of tert-butyl(S)-3-((R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-carboxylate

Using the general coupling procedure outline in Route R, Intermediate28.0 was couple with (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylicacid to provide the desired product. LCMS-APCI (POS.) m/z: 384.2(M+H-Boc)+.

Step 2: Preparation of(R)-1-((S)-piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamidehydrochloride

To a solution of tert-butyl(S)-3-((R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-carboxylate(0.580 g, 1.20 mmol) in DCM (10.0 mL) at rt was added TFA (2.0 mL, 26.1mmol). The solution was allowed to stir at rt for two hours. Thesolution was concentrated to dryness under reduced pressure to afford(R)-1-((S)-piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide(0.588 g, 1.18 mmol) as an off-white solid. LCMS-APCI (POS.) m/z: 384.2(M+H)+.

Intermediate 28.11:(R)—N-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamide

Step 1: Preparation of tert-butyl(R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate

A solution of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid(0.200 g, 0.872 mmol) and DIPEA (0.289 mL, 1.75 mmol) in DMF (2 mL) wascooled to 0° C. HBTU (0.496 g, 1.31 mmol) was added and the reactionallowed to stir at 0° C. for one minute.4-(trifluoromethyl)phenyl)methanamine (0.183 g 1.05 mmol) was then addedand the reaction mixture was allowed to warm to rt and stir for 20 min.The reaction was then washed with a saturated aqueous NaHCO₃, and theaqueous layer was extracted with DCM (5×10 mL). The combined organiclayers were dried over MgSO₄ and concentrated under reduced pressure.The crude material was purified by MPLC using silica gel and eluted witha gradient of 10-100% EtOAc in hexane, to provide tert-butyl(R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate(0.202 g, 0.523 mmol) as a white solid. LCMS-APCI (POS.) m/z: 287.1(M+H-Boc)+.

Step 2: Preparation of(R)—N-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamide

To a solution of tert-butyl(R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate(0.200 g, 0.518 mmol) in DCM (1.0 mL) at rt was added TFA (5.0 mL, 65.4mmol). The solution was allowed to stir at rt for 2 h and thenconcentrated to dryness under reduced pressure to afford the desiredproduct (0.207 g, 0.641 mmol) as an off-white solid. LCMS-APCI (POS.)m/z: 287.2 (M+H)+.

The compounds set forth in the following table were synthesizedfollowing the procedure described for Intermediate 28.11 using knownstarting material replacements as described. HCl can also be used toremove the Boc groups to give the HCl salts.

TABLE 8 Boc-Amino Intermediate Amine Acid Structure, Name and Data 28.04-CF₃- benzylamine D-N-Boc-proline

(R)-N-(4-(trifluoromethyl)benzyl) pyrrolidine-2- carboxamidehydrochloride LCMS-APCI (POS.) m/z: 273.1 (M + H)+ 28.1 Intermediate 9.5

(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide2,2,2- trifluoroacetate 28.2 Intermediate 9.5 D-N-Boc-proline

(R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)pyrrolidine-2- carboxamide2,2,2-trifluoroacetate 28.3 Intermediate 9.5

(2R,4S)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoropyrrolidine-2- carboxamide2,2,2-trifluoroacetate 28.4 Intermediate 9.2

(1R,3R,5R)-N-((R)-(4-chloro-2,5- difluorophenyl)(cyclopropyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride 28.X Intermediate8.0

(1R,3R,5R)-N-((R)-(-2,5-difluoro-4-trifluoromethylphenyl)(cyclopropypmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride 28.8 Intermediate8.0

(2R,4R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-4-hydroxypyrrolidine- 2-carboxamide2,2,2-trifluoroacetate 28.11 4-CF3- benzyl-amine

(R)-N-(4-(trifluoromethyl)benzyl)piperidine-2- carboxamide hydrochloride28.12 (S)-1-(4- chlorophenyl)- ethan-1-amine (Eurofins LancasterLaboratories,

LLC.) (R)-N-((S)-1-(4-chlorophenyl)ethyl) piperidine-2- carboxamide2,2,2-trifluoroacetate LCMS-APCI (POS.) m/z: 267.1 (M + H)+ 28.13(R)-1-(4- chlorophenyl)- ethan-1-amine (Alpha Aesar)

(R)-N-((R)-1-(4-chlorophenyl)ethyl)piperidine-2- carboxamide2,2,2-trifluoroacetate LCMS-APCI (POS.) m/z: 267.1 (M + H)+ 28.14(S)-1-(3,4- dichlorophenyl)- ethan-1-amine (Enamine, Ltd.)

(R)-N-((S)-1-(3,4-dichlorophenyl)ethyl)piperidine-2- carboxamide2,2,2-trifluoroacetate LCMS-APCI (POS.) m/z: 301.1 (M + H)+ 28.15(R)-1-(3,4- dichlorophenyl)- ethan-1-amine (Enamine, Ltd.)

(R)-N-((R)-1-(3,4-dichlorophenyl)ethyl)piperidine-2- carboxamide2,2,2-trifluoroacetate LCMS-APCI (POS.) m/z: 301.1 (M + H)+ 28.17(1r,3r)-3- (trifluoro- methyl)cyclo- butan-1-amine (Enamine, Ltd.)

(R)-4,4-difluoro-N-((1r,3R)-3-(trifluoromethyl)cyclobutyl)pyrrolidine-2-carboxamide2,2,2-trifluoroacetate LCMS-APCI (POS.) m/z: 273.2 (M + H)+ 28.18(4-(trifluoro- methyl)phenyl)- methanamine (Chem-Implex International,Inc.)

(Combi-Blocks, (R)-N-(4-(trifluoromethyl)benzyl)-5- Inc.)azaspiro[2.4]heptane-6-carboxamide 2,2,2- trifluoroacetate LCMS-APCI(POS.) m/z: 299.2 (M + H)+ 28.19 (4-(trifluoro- methyl)phenyl)-methanamine (Chem-Implex International, Inc.)

(Advanced (R)-N-(4-(trifluoromethyl)benzyl)azetidine-2- ChemBlocks,carboxamide 2,2,2-trifluoroacetate Inc.) LCMS-APCI (POS.) m/z: 259.2(M + H)+ 28.20 (4-(trifluoro- methyl)phenyl)- methanamine (Chem-ImplexInternational, Inc.) N-(tert-butoxycarbonyl)- N-methyl-D-alanine(Combi-Blocks, Inc.)

(R)-2-(methylamino)-N-(4- (trifluoromethyl)benzyl)propenamide 2,2,2-trifluoroacetate LCMS-APCI (POS.) m/z: 261.2 (M + H)+ 28.21(4-(trifluoro- methyl)phenyl)- methanamine (Chem-Implex International,Inc.)

(Watanabe ((2R,4S)-4-fluoro-N-(4- Chemical(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide Industries, Ltd.)2,2,2-trifluoroacetate LCMS-APCI (POS.) m/z: 291.1 (M + H)+ 28.22(4-(trifluoro- methyl)phenyl)- methanamine (Chem-Implex International,Inc.)

(2R,4S)-4-fluoro-N-(4- (trifluoromethyl)benzyl)pyrrolidine-2-carboxamide2,2,2-trifluoroacetate LCMS-APCI (POS.) m/z: 309.1 (M + H)+ 28.24(4-(trifluoro- methyl)phenyl)- methanamine (Chem-Implex International,Inc.)

(PharmaBlock, (2R,4S)-4-fluoro-N-(4- Inc.)(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide 2,2,2-trifluoroacetateLCMS-APCI (POS.) m/z: 301.1 (M + H)+ 28.25 (R)-1-(4- (trifluoro-methyl)phenyl)- ethan-1-amine (Enamine, Ltd.)

(2R,4S)-4-fluoro-N-(4- (trifluoromethyl)benzyl)pyrrolidine-2-carboxamide2,2,2-trifluoroacetate LCMS-APCI (POS.) m/z: 323.2 (M + H)+ 28.26(6-(trifluoro- methyl)pyridin- 3-yl)methan- amine (Combi- Blocks, Inc.)

(2R,4S)-4-fluoro-N-(4- (trifluoromethyl)benzyl)pyrrolidine-2-carboxamide2,2,2-trifluoroacetate LCMS-APCI (POS.) m/z: 310.2 (M + H)+

Intermediate 28.5 Preparation of(1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide

Step 1: Preparation of 2-benzyl 3-ethyl(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

To a 0° C. solution of ethyl ester cyclopropyl proline (10.0 g, 64.4mmol) in dry DCM (500 mL) was added DIPEA (24.7 mL, 141.8 mmol) followedby slow addition of benzyl chloroformate (9.6 mL, 67 mmol). Bothadditions were monitored to ensure reaction temperature did not riseabove 10° C. The mixture was allowed to slowly warm to rt and stirredfor 4 h and then quenched with saturated aqueous NH₄Cl, saturatedaqueous NaHCO₃, brine, dried, and concentrated under reduced pressure togive a yellow oil which was purified by silica gel chromatography (0-30%EtOAc in hexanes) to give a colorless oil (13.8 g). LCMS-APCI (POS.)m/z: 290.1 (M+H)+.

Step 2: Preparation of(1R,3R,5R)-2-((benzyloxy)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid

To a solution of the ethyl ester (11.7 g, 45.8 mmol) in EtOH (120 mL)was added a solution of lithium hydroxide monohydrate (2.31 g, 55.0mmol) in water (60 mL) over 5 minutes while maintaining the reactiontemperature below 30 C. The reaction was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressure.The residue was partitioned between water and MTBE. The aqueous layerwas collected and the organic layer discarded. The aqueous layer wasthen acidified to pH 1-2 by addition of 2N HCl. The aqueous layer wasthen extracted with DCM. The combined organic extracts were dried oversodium sulfate and the solvent concentrated to give the desired acid.Acid was used in next step without further purification. (0.8 g).LCMS-APCI (NEG.) m/z: 260.1 (M−H)+.

Step 3: Preparation of benzyl(1R,3R,5R)-3-(((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

To the starting acid was combined with HBTU (3.98 g, 10.5 mmol), HOBt(1.42 g, 10.5 mmol), amine (2.18 g, 7.0 mmol), and acid (2.0 g, 7.69mmol). To the solids were added NMP (15 mL), followed by DIEA (3.65 mL,21 mmol). The resulting mixture was stirred at room temperature for 20minutes. It was diluted with 125 mL ethyl acetate and washed withsaturated aqueous sodium bicarbonate (125 mL), water (2×100 mL),ammonium chloride (1×100 ml) and brine. The organic phase was dried oversodium sulfate and concentrated to a viscous oil which was purified withsilica gel using a gradient to 50% ethyl acetate/hexanes, providing thedesired product as a white foam. (2.51 g). LCMS-APCI (POS.) m/z: 493.2(M+H)+.

Step 4: Preparation of(1R,3R,5R)—N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide

The starting material (2.04 g, 4.25 mmol) was combined with palladium oncarbon (0.2 g) and to the solids was added MeOH (10 mL). The resultingmixture was sparged with hydrogen from a hydrogen balloon for 2 minutesand then the flask was evacuated and backfilled with hydrogen fourtimes. The resulting mixture was stirred under balloon pressure hydrogenfor 45 minutes. Observed by LC/MS was clean desired product. Thereaction was filtered through Celite followed by a syringe filter andconcentrated under reduced pressure, providing the pure desired productas a glassy solid/white foam (1.48 g). LCMS-APCI (POS.) m/z: 359.1(M+H)+.

The compounds set forth in the following table were synthesizedfollowing the procedure described for Intermediate 28.5 using knownstarting material replacements as described.

Intermediate Amine C-Amino Acid Structure, Name and Data 28.5Intermediate 29.9

(1R,3R,5R)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 28.6 Intermediate 29.1

(1R,3R,5R)-N-((R)-(4-chloro-2,5- difluorophenyl)(oxetan-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 28.7 Intermediate 29.10

(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 28.9 Intermediate 29.10

(2R,4R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-4-hydroxypyrrolidine-2-carboxamide 28.10 Intermediate 29.1

(2R,4S)-N-((R)-(4-chloro-2,5- difluorophenyl)(oxetan-3-yl)methyl)-4-hydroxypyrrolidine-2-carboxamide

Intermediate 29.1: Preparation of(R)-(4-chloro-2,5-difluorophenyl)(oxetan-3-yl)methanamine hydrochloride

Step 1: Preparation of(S,E)-2-methyl-N-(oxetan-3-ylmethylene)propane-2-sulfinamide

To a solution of oxetan-3-ylmethanol (2.0 g, 22.7 mmol) in DCM (20 mL)at 0° C. was added Dess-Martin periodinane (14.4 g, 34.0 mmol) portionwise. The ice bath was removed, and the resulting suspension was stirredat room temperature for 1.5 h. The reaction mixture was filtered throughCelite, and the filtrate was partially concentrated under reducedpressure (water bath temperature 10-15° C. to prevent evaporation ofaldehyde) so that approximately 10 mL of DCM remained. The resultingsuspension was filtered again through Celite, and the filtered solid wasrinsed with a minimum amount of DCM. To the filtrate was washed withadded additional DCM (10 mL), and the resulting mixture was cooled to 0C with an ice bath. (S)-2-methylpropane-2-sulfinamide (3.0 g, 25.0 mmol)was added portion wise, followed by titanium isopropoxide (9.7 g, 34.1mmol). The ice bath was removed, and the reaction mixture was stirred atroom temperature for 1 hour. The mixture was carefully poured intosaturated aqueous NaHCO₃ (gas evolution) and then stirred vigorously atroom temperature for 30 min. The suspension was filtered through Celiteand the filter cake was washed with DCM (20 mL). The filtrate wastransferred to a separatory funnel, the layers were separated, and thecombined were dried over Na₂SO₄ and concentrated under reduced pressure.The remaining viscous oil was purified with silica gel (0-50% ethylacetate in hexanes) to provide the desired product (1.2 g, 6.3 mmol) asa viscous yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (d, J=4.3 Hz,1H), 4.80 (ddd, J=2.7, 6.0, 8.4 Hz, 2H), 4.65 (dt, J=6.1, 14.9 Hz, 2H),4.11 (ttd, J=4.3, 6.3, 8.4 Hz, 1H), 1.14 (s, 10H).

Step 2: Preparation of(S)—N-(®-(4-chloro-2,5-difluorophenyl)(oxetan-3-yl)methyl)-2-methylpropane-2-sulfinamide

To an oven-dried 500 mL round bottom flask under a nitrogen atmospherewas added 1-chloro-2,5-difluoro-4-iodobenzene (9.93 g, 36.18 mmol) in175 mL anhydrous THF. The resulting solution was cooled to −100° C. witha diethyl ether/liquid nitrogen bath, and then n-BuLi solution (1.6M inTHF, 22.6 mL, 36.2 mmol) was added dropwise so that the internaltemperature remained between −90 and −100° C. The resulting yellowcolored mixture was stirred between −90 and −100 C for 30 min and then(S,E)-2-methyl-N-(oxetan-3-ylmethylene)propane-2-sulfinamide (7.53 g,39.80 mmol) in 15 mL THF was added dropwise via syringe so that theinternal temperature remained between −90 and −100° C. The resultingmixture was stirred between −90 and −100° C. for 30 min and thenquenched at the same temperature by dropwise addition of saturated NH₄Clsolution followed by warming to room temperature. The mixture wasdiluted with 150 mL water and 150 mL EtOAc. The layers were shaken andseparated and the organic phase was washed with saturated NaCl solution,dried over Na₂SO₄, and concentrated to a viscous nearly colorless oilwhich was purified by MPLC using silica gel (0-100% ethylacetate/hexanes) to provide the desired single diastereomer (6.88 g,20.38 mmol) as a white foam. LCMS-APCI (POS.) m/z: 338.1 (M+H)+

Step 3: Preparation of(R)-(4-chloro-2,5-difluorophenyl)(oxetan-3-yl)methanamine hydrochloride,Intermediate 29.1

(S)—N—((R)-(4-chloro-2,5-difluorophenyl)(oxetan-3-yl)methyl)-2-methylpropane-2-sulfinamide(6.88 g, 20.35 mmol) was dissolved in methanol and cooled to 0° C. withan ice bath. HCl (4N in 1,4-dioxane, 6.11 mL, 24.42 mmol) was addeddropwise using a syringe and the resulting mixture was stirred at 0° C.for 5 minutes before the ice bath was removed. The reaction was stirredat rt for 45 minutes and then quenched with triethylamine (28 mL). Theresulting mixture was concentrated under reduced pressure to provide awhite solid. The solid was partitioned between saturated NaHCO₃ solutionand DCM. The layers were separated and the aqueous phase was extractedwith additional DCM. The organic extracts were combined, dried overNa₂SO₄ and concentrated under reduced pressure, providing the desiredproduct (6.18 g, 18.28 mmol) as a viscous oil (the purity was estimatedto be 70%). This material was converted to the HCl salt by the addition1 equivalent of 4N HCl in dioxane followed by concentration underreduced pressure to give a white solid. ¹H NMR (400 MHz, methanol-d₄) δ7.30-7.41 (m, 2H), 4.85 (dd, J=6.3, 7.7 Hz, 1H), 4.68 (t, J=6.2 Hz, 1H),4.60 (dd, J=6.4, 8.0 Hz, 1H), 4.50 (d, J=1.1, 9.8 Hz, 1H), 4.33 (td,J=1.0, 6.4 Hz, 1H), 3.33 (dh, J=1.6, 3.4 Hz, 2H).

The compounds set forth in the following table were synthesizedfollowing the procedure described for intermediate 29.1 using knownstarting material replacements as described

TABLE 9 Intermediate Aryl halide Structure, Name and Data 29.2 1-bromo-2,4- difluoro- benzene

(R)-(2,4-difluorophenyl)(oxetan-3- yl)methanamine hydrochlorideLCMS-APCI (POS.) m/z: 200.2 (M + H)+; ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.46 (td, J = 6.6, 8.6 Hz, 1H), 7.22 (ddd, J = 2.6, 9.4, 10.7 Hz, 1H),7.09 (tdd, J = 1.1, 2.6, 8.6 Hz, 1H), 5.68 (d, J = 7.1 Hz, 1H), 4.85(dd, J = 7.0, 10.6 Hz, 1H), 4.68 (dd, J = 6.5, 7.6 Hz, 1H), 4.53 (t, J =6.2 Hz, 1H), 4.44 (dd, J = 6.2, 7.9 Hz, 1H), 3.49 (dq, J = 7.0, 14.8 Hz,1H), 1.03 (s, 9H). 29.3 1-bromo-4- (trifluoro- methyl) benzene

(R)-oxetan-3-yl(4- (trifluoromethyl)phenyl)methanamine hydrochlorideLCMS-APCI (POS.) m/z: 232.1 (M + H)+ 29.4 4-chloro-2- fluoro-1-iodobenzene

(R)-(4-chloro-2- fluorophenyl)(oxetan-3-yl)methanamine hydrochlorideLCMS-APCI (POS.) m/z: 216.0 (M + H)+ 29.5 4-bromo-1- chloro-2- fluoro-benzene

(R)-(4-chloro-3- fluorophenyl)(oxetan-3-yl)methanamine hydrochlorideLCMS-APCI (POS.) m/z: 216.0 (M + H)+ 29.6 2-fluoro-4- iodo-1-(trifluoro- methyl) benzene

(R)-(3-fluoro-4- (trifluoromethyl)phenyl)(oxetan-3-yl) methanaminehydrochloride LCMS- APCI (POS.) m/z: 250.0 (M + H)+ 29.7 1-bromo-4-chloro- benzene

(R)-(4-chlorophenyl)(oxetan-3- yl)methanamine hydrochloride LCMS-APCI(POS.) m/z: 198.1 (M + H)+ 29.8 (3-fluoro- oxetan-3-yl) methanol

(S)-(4-chloro-2,5-difluorophenyl)(3- fluorooxetan-3-yl)methanamineLCMS-APCI (POS.) m/z: 252.1 (M + H)+

Intermediate 30.0: 3-methyl-5-(methylsulfonyl)benzoic Acid

Step 1: Preparation of methyl 3-methyl-5-(methylthio)benzoate

Methyl 3-bromo-5-methylbenzoate (4.00 g, 17.5 mmol), sodiummethanethiolate (1.35 g, 19.2 mmol),tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃) (0.120 g, 0.131mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.152g, 0.262 mmol) and DIPEA (3.74 mL, 20.9 mmol) were added to a 250 mLround-bottom flask equipped with a condenser. The flask was evacuated ofair and backfilled with nitrogen three times. Dry toluene (40.0 ml) wasadded to the mixture, and it was stirred at 90° C. for twelve hours. Tothe reaction was subsequently added sodium methanethiolate (0.183 g,2.62 mmol) followed by DIPEA (0.456 mL, 2.62 mmol) and the reactionstirred at 90° C. for two hours. The reaction mixture was cooled to roomtemperature and quenched with 1N aqueous hydrochloric acid solution, andextracted with EtOAc. The organic layer was washed with saturated NaClsolution and dried over MgSO₄. The organic layer was concentrated underreduced pressure, and the crude material was purified by MPLC usingsilica gel and eluted with a gradient of 0-7% EtOAc/hexanes to givemethyl 3-methyl-5-(methylthio)benzoate (1.89 g, 9.63 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.56 (dtd, J=0.8, 1.5, 11.3 Hz, 2H), 7.37 (td,J=0.8, 1.7 Hz, 1H), 3.85 (s, 3H), 2.35 (q, J=0.7 Hz, 3H).

Step 2: Preparation of methyl 3-methyl-5-(methylsulfonyl)benzoate

To a solution of methyl 3-methyl-5-(methylthio)benzoate (1.00 g, 5.10mmol) in DCM (25.0 mL) was added 3-chloroperoxybenzoic acid (2.40 g,10.7 mmol, 77 wt %) in small portions over ten minutes. The mixture wasstirred for one hour at 22° C. The reaction was quenched with saturatedNaHCO₃ solution (40.0 mL). The reaction became clear from turbid. Theaqueous phase was then extracted with DCM (60 mL), the organic layerswere combined and washed with aqueous saturated NaHCO₃ solution (2×20mL) and saturated NaCl solution (20 mL). The organic layer was driedover Na₂SO₄ and the solvents were removed under reduced pressure. Thecrude material was purified by MPLC using silica gel and eluted with agradient of 20-60% EtOAc/hexanes to give methyl3-methyl-5-(methylsulfonyl)benzoate (1.05 g, 4.60 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.22 (td, J=0.8, 1.8 Hz, 1H), 8.11 (dq, J=0.8, 1.7Hz, 1H), 8.05 (td, J=0.8, 1.7 Hz, 1H), 3.91 (s, 3H), 3.27 (s, 3H).

Step 3: Preparation of 3-methyl-5-(methylsulfonyl)benzoic Acid

To a solution of methyl 3-methyl-5-(methylsulfonyl)benzoate (1.03 g,4.51 mmol) in methanol (8.0 mL) and water (8.0 mL) was added potassiumhydroxide (0.633 g, 11.3 mmol) portion wise, and the mixture was heatedat 60° C. for five hours. The mixture was concentrated under reducedpressure and the resulting residue was acidified to pH 2-3 with HCl(3N). The resulting white solid was filtered off and washed with waterto give pure 3-methyl-5-(methylsulfonyl)benzoic acid (0.920 g, 4.29mmol). LCMS-APCI (POS.) m/z: 215.1 (M+H)+.

The compounds set forth in the following table were synthesizedfollowing the procedure described above using known starting materialreplacements as described.

TABLE 10 Intermediate Aryl Bromide Structure, Name and Data 30.1 methyl3-bromo- 5-fluorobenzoate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.87 (s, 1H), 8.25 (t, J = 1.5 Hz, 1H),8.06 (dddd, J = 1.5, 2.5, 8.8, 24.6 Hz, 2H), 3.35 (S, 3H)..

Intermediate 31.1:(1R,3R,5R)-2-(2-(tert-butyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid

Step 1: Preparation of 3-benzyl 2-(tert-butyl)(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

To a solution of(1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (1.52 g, 6.70 mmol) in DMF (5.0 mL) was added potassium carbonate(1.03 g, 7.37 mmol). The resulting mixture was cooled to 0° C. and thenbenzyl bromide (0.96 mL, 8.05 mmol) was added dropwise over fiveminutes. The resulting mixture was allowed to warm to 22° C. and stirredovernight. It was diluted with EtOAc (70 mL) and washed 4 times withwater (200 mL total volume). The organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. The crude material was purified byMPLC using silica gel and eluted with a gradient of 0-15% EtOAc/hexanesto provide 3-benzyl 2-(tert-butyl)(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2.08 g, 6.56mmol) as a colorless, viscous oil. LCMS-APCI (POS.) m/z: 218.1(M+H-Boc)+.

Step 2: Preparation of benzyl(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate hydrochloride

To a solution of 3-benzyl 2-(tert-butyl)(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2.08 g, 6.56mmol) in DCM (6.0 mL) at 22° C. was added TFA (6.0 mL, 78.4 mmol). Thesolution was allowed to stir at 22° C. for thirty minutes. The solutionwas concentrated to dryness under reduced pressure to afford benzyl(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate hydrochloride (2.15g, 6.51 mmol) as an off-white solid. LCMS-APCI (POS.) m/z: 218.1 (M+H)+.

Step 3: Preparation of benzyl(1R,3R,5R)-2-(2-(tert-butyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate

Benzyl (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate hydrochloride(0.450 g, 1.36 mmol), O-(Benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (0.78 g, 2.04 mmol), benzotriazol-1-ol (0.28 g, 2.04mmol) and 2-(tert-butyl)isonicotinic acid (0.269 g, 1.50 mmol) wereadded to a flask and NMP (5.0 mL) was added, followed byN,N-diisopropylethylamine (0.71 mL, 4.08 mmol). The resulting mixturewas stirred at 22° C. for 20 minutes. The reaction was diluted withEtOAc (60 mL) and saturated NaHCO₃ (70 mL) solution. The layers wereshaken vigorously and the organic phase was washed again with saturatedNaHCO₃ solution, twice with water, and once with saturated sodiumchloride solution. The organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. The remaining viscous oil waspurified by MPLC using silica gel and eluted with a gradient of 0-30%EtOAc/hexanes, providing benzyl(1R,3R,5R)-2-(2-(tert-butyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate(0.386 g, 1.02 mmol) as a colorless glassy solid. LCMS-APCI (POS.) m/z:379.2 (M+H)+.

Step 4: Preparation of(1R,3R,5R)-2-(2-(tert-butyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid

A solution of benzyl(1R,3R,5R)-2-(2-(tert-butyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate(0.386 g, 1.02 mmol) in THF (3.0 mL) and EtOAc (3.0 mL) was prepared.The flask was evacuated and backfilled with hydrogen (balloon pressure)and stirred for eighteen hours at 22° C. The reaction was diluted withmethanol (10.0 mL) and filtered through a syringe filter and thenconcentrated under reduced pressure, providing(1R,3R,5R)-2-(2-(tert-butyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (0.285 g, 0.988 mmol) as a white foam. LCMS-APCI (POS.) m/z: 289.2(M+H)+.

The compounds set forth in the following table were synthesizedfollowing the procedure outlined above using known starting materialreplacements as described.

TABLE 11 Aryl Inter- Proline carboxylic mediate derivative acidStructure, Name and Data 31.0 benzyl D-proline hydrochlorideIntermediate 13.11

(3-((5-azaspiro[2.3]hexan-5- yl)sulfonyl)benzoyl)-D-proline LCMS-APCI(POS.) m/z: 363.1 (M − H)− 31.2 benzyl (1R,3R,5R)- 2-azabicyclo[3.1.0]-hexane-3-carboxylate 3-(tert- butyl)benzoic acid

(1R, 3R,5R)-2-(3-(tert-butyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid LCMS-APCI (POS.) m/z: 288.2(M + H)+ 31.3 benzyl (1R,3R,5R)- 2-azabicyclo[3.1.0]-hexane-3-carboxylate 2-(difluoro- methyl)iso- nicotinic acid

(1R, 3R,5R)-2-(2-(difluoromethyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid LCMS-APCI (POS.) m/z: 283.1(M + H)+ 31.4 benzyl (1R,3R,5R)- 2-azabicyclo[3.1.0]-hexane-3-carboxylate 3- (ethyl- sulfonyl)benzoic acid

(1R,3R,5R)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid LCMS-APCI (POS.) m/z: 324.1(M + H)+ 31.5 benzyl (1R,3R,5R)- 2-azabicyclo[3.1.0]-hexane-3-carboxylate 2-methoxy-5- (methylsulfonyl) benzoic acid

(1R,3R,5R)-2-(2-methoxy-5- (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid LCMS-APCI (POS.) m/z: 340.1(M + H)+ 31.6

3- (methylsulfonyl) benzoic acid

(2R,4S)-4-fluoro-1-(3- (methylsulfonyl)benzoyl)pyrrolidine-2- carboxylicacid LCMS-APCI (POS.) m/z: 316.3 (M − H)+ 31.7

2-methoxy-5- (methylsulfonyl) benzoic acid

(2R,4S)-4-fluoro-1-(2-methoxy-5- (methylsulfonyl)benzoyl)pyrrolidine-2-carboxylic acid LCMS-APCI (POS.) m/z: 346.3 (M − H)+ 31.8 benzyl(1R,3R,5R)- 2-azabicyclo[3.1.0]- hexane-3-carboxylate 2- (trifluoro-methyl)iso- nicotinic acid

(1R,3R,5R)-2-(2-(trifluoromethyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid LCMS-APCI (POS.) m/z: 299.3(M − H)+

Intermediate 32.0: Preparation of 3-(3-(((benzyloxy)carbonyl)amino)oxetan-3-yl)benzoic Acid

Step 1: Preparation of 3-(3-aminooxetan-3-yl)benzaldehyde hydrochloride

3-Bromobenzaldehyde diethyl acetal (11.65 g, 45 mmol) in dry THF (100mL) at −78° C. was added n-butyl lithium (2.5 M in hexanes, 19 mL, 47mmol) dropwise. The sample was stirred at −78° C. for ten minutes thenadded 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfonamide (7.5 g, 43mmol) dropwise. The sample was stirred at −78° C. for one hour. Themixture was diluted with 200 mL saturated ammonium chloride solution and200 mL ethyl acetate. The layers were shaken and separated and theorganic phase was dried over magnesium sulfate and concentrated underreduced pressure. The crude mixture was dissolved in ethyl acetate (250mL). The reaction mixture was cooled to 0° C. was added 1M hydrochloricacid in ethyl acetate dropwise (24 mL, 24 mmol). The reaction mixturewas stirred at 0° C. for one hour then vacuum filtered to give thedesired product as a slightly off white solid (1.97 g, 9.2 mmol). ¹H NMR(400 MHz, DMSO-d₆) δ 10.08 (s, 1H), 9.18 (s, 3H), 8.09 (s, 1H), 8.01 (d,J=7.9 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.79-7.73 (m, 1H), 5.03-4.91 (m,4H).

Step 2: Preparation of benzyl (3-(3-formylphenyl)oxetan-3-yl)carbamate

3-(3-Aminooxetan-3-yl)benzaldehyde hydrochloride (1.97 g, 9.2 mmol) indry dichloromethane (20 mL) at 0° C. was added diisopropylethylamine(4.8 mL, 28 mmol) followed by benzyl chloroformate (1.6 mL, 11 mmol)dropwise. The reaction mixture was stirred at 0° C. for thirty minutes.The mixture was diluted with 150 mL water and 150 mL dichloromethane.The layers were shaken and separated and the organic phase was washedwith saturated sodium chloride solution, dried over magnesium sulfate,concentrated under reduced pressure, and purified by silica gelchromatography with a gradient to 50% ethyl acetate/hexanes to give thedesired product as a clear colorless oil (2.29 g, 7.3 mmol). APCI (POS.)m/z: 312.10 (M+H)+. ¹H NMR (400 MHz, dichloromethane-d₂) δ 10.04 (s,1H), 8.04 (s, 1H), 7.92-7.82 (m, 2H), 7.67-7.57 (m, 1H), 7.49-7.26 (m,5H), 5.80 (s, 1H), 5.12 (s, 2H), 5.05-4.84 (m, 4H).

Step 3: Preparation of3-(3-(((benzyloxy)carbonyl)amino)oxetan-3-yl)benzoic acid, Intermediate32.0

Benzyl (3-(3-formylphenyl)oxetan-3-yl)carbamate (2.29 g, 7.3 mmol) inchloroform (24 mL), acetonitrile (24 mL), and water (36 mL) was addedsodium periodate (7.86 g, 37 mmol) followed by ruthenium(III)trichloride monohydrate (0.083 g, 0.37 mmol). The reaction mixture wasstirred for one hour. The mixture was diluted with 150 mL water and 150mL 10% methanol in dichloromethane. The layers were shaken and separatedand the organic phase was washed with saturated sodium chloridesolution, dried over magnesium sulfate, and concentrated under reducedpressure to give the desired product as a black solid (1.872 g, 5.7mmol). LCMS-APCI (NEG.) m/z: 326.10 (M−H)−. ¹H NMR (400 MHz,Methanol-d₄) δ 8.25 (s, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.87-7.74 (m, 1H),7.58-7.47 (m, 1H), 7.44-7.11 (m, 5H), 5.10 (s, 2H), 5.05-4.80 (m, 4H).

Intermediate 33.0: Preparation of 3-(3-methyloxetan-3-yl)benzoic Acid

Step 1: Preparation of diethyl 2-(3-(1,3-dioxolan-2-yl)phenyl)malonate

Bis(dibenzylideneacetone)palladium(0) (0.068 g, 0.12 mmol) and potassiumphosphate tribasic were combined (3.788 g, 18 mmol) under a nitrogenatmosphere. 2-(3-Bromophenyl)-1,3-dioxolane (0.900 mL, 5.9 mmol),diethyl malonate (0.993 mL, 6.5 mmol), tri-tert-butylphosphanate (0.058mL, 0.24 mmol) and dry toluene (18 mL) were added to the reactionmixture, heated at 70 C, and stirred for 3 days. The reaction mixturewas filtered through Celite, concentrated under reduced pressure, andpurified by silica gel chromatography with a gradient to 30% ethylacetate/hexanes to give the desired product as a clear yellow oil (0.324g, 1.0 mmol). APCI (POS.) m/z: 309.10 (M+H)+. ¹H NMR (400 MHz,dichloromethane-d₂) δ 7.53-7.39 (m, 4H), 5.81 (s, 1H), 4.67 (s, 1H),4.28-4.18 (m, 4H), 4.17-4.02 (m, 4H), 1.29 (t, J=7.1 Hz, 6H).

Step 2: Preparation of diethyl2-(3-(1,3-dioxolan-2-yl)phenyl)-2-methylmalonate

Diethyl 2-(3-(1,3-dioxolan-2-yl)phenyl)malonate (0.324 g, 1.0 mmol),methyl iodide (0.065 mL, 1.0 mmol), and 21% sodium ethoxide in ethanol(0.785 mL, 2.1 mmol) were combined, heated at 78° C., and stirred forone hour. The reaction mixture was diluted with 50 mL water and 50 mLethyl acetate. The layers were shaken and separated and the organicphase was dried over magnesium sulfate, concentrated under reducedpressure, and purified by silica gel chromatography with a gradient to30% ethyl acetate/hexanes to give the desired product as a clearcolorless oil (0.244 g, 0.76 mmol). APCI (POS.) m/z: 323.10 (M+H)+. ¹HNMR (400 MHz, dichloromethane-d₂) δ 7.50-7.48 (m, 1H), 7.46-7.38 (m,3H), 5.80 (s, 1H), 4.30-4.19 (m, 4H), 4.17-4.00 (m, 4H), 1.87 (s, 3H),1.28 (t, J=7.1 Hz, 6H).

Step 3: Preparation of2-(3-(1,3-dioxolan-2-yl)phenyl)-2-methylpropane-1,3-diol

Diethyl 2-(3-(1,3-dioxolan-2-yl)phenyl)-2-methylmalonate (0.244 g, 0.76mmol) in dry THF (6 mL) at 0° C. was added 2.4M lithium aluminum hydridein THF (0.63 mL, 1.5 mmol) dropwise. The reaction mixture was heated at66° C. overnight. The reaction mixture was cooled to 0° C., added water(0.057 mL), followed by the addition of 1M sodium hydroxide in water(0.057 mL), followed by the addition of water (0.171 mL). The reactionmixture stirred for thirty minutes at room temperature, filtered throughCelite, concentrated under reduced pressure, and purified by silica gelchromatography with a gradient to 100% ethyl acetate/hexanes to give thedesired product as a clear colorless oil (0.116 g, 0.48 mmol). APCI(POS.) m/z: 239.10 (M+H)+. ¹H NMR (400 MHz, dichloromethane-d₂) δ7.56-7.54 (m, 1H), 7.50-7.46 (m, 1H), 7.44-7.37 (m, 2H), 5.78 (s, 1H),4.19-4.10 (m, 2H), 4.09-4.02 (m, 2H), 3.97-3.93 (m, 2H), 3.86-3.81 (m,2H), 1.30 (s, 3H).

Step 4: Preparation of 2-(3-(3-Methyloxetan-3-yl)phenyl)-1,3-dioxolane

2-(3-(1,3-Dioxolan-2-yl)phenyl)-2-methylpropane-1,3-diol (0.116 g, 0.48mmol) in dry THF (1.5 mL) at −78° C. was added 1.6M n-butyl lithium inhexanes (0.30 mL, 0.48 mmol) dropwise. The reaction mixture was stirredat −78° C. for ten minutes then added 4-toluenesulfonyl chloride (0.092g, 0.48 mmol) in dry THF (1.5 mL) dropwise followed by 1.6M n-butyllithium in hexanes (0.30 mL, 0.48 mmol) dropwise. The reaction mixturewas heated at 70° C. overnight. The reaction mixture was cooled to 0°C., The reaction mixture was diluted with 50 mL water and 50 mL ethylacetate. The layers were shaken and separated and the organic phase wasdried over magnesium sulfate, concentrated under reduced pressure,purified by silica gel chromatography with a gradient to 50% ethylacetate/hexanes to give the desired product as a clear colorless oil(0.040 g, 0.18 mmol). APCI (POS.) m/z: 221.15 (M+H)+. ¹H NMR (400 MHz,dichloromethane-d₂) δ 7.43-7.32 (m, 3H), 7.27-7.23 (m, 1H), 5.79 (s,1H), 4.98-4.94 (m, 2H), 4.65-4.62 (m, 2H), 4.19-3.99 (m, 4H), 1.75 (s,3H).

Step 5: Preparation of 3-(3-methyloxetan-3-yl)benzaldehyde

2-(3-(3-Methyloxetan-3-yl)phenyl)-1,3-dioxolane (0.040 g, 0.18 mmol) indichloromethane (1.5 mL) was added trifluoroacetic acid (0.139 mL, 1.8mmol). The reaction mixture was stirred for one hour, concentrated underreduced pressure, and purified by silica gel chromatography with agradient to 50% ethyl acetate/hexanes to give the desired product as aclear colorless oil (0.030 g, 0.17 mmol). APCI (POS.) m/z: 177.10(M+H)+. ¹H NMR (400 MHz, dichloromethane-d₂) δ 10.05 (s, 1H), 7.81-7.75(m, 2H), 7.62-7.57 (m, 1H), 7.57-7.53 (m, 1H), 5.00-4.97 (m, 2H),4.72-4.68 (m, 2H), 1.79-1.77 (m, 3H).

Step 6: Preparation of 3-(3-methyloxetan-3-yl)benzoic acid, Intermediate33.0

3-(3-Methyloxetan-3-yl)benzaldehyde (0.030 g, 0.17 mmol) in chloroform(1 mL), acetonitrile (1 mL), and water (1.5 mL) was added sodiumperiodate (0.181 g, 0.85 mmol) followed by ruthenium(III) trichloridemonohydrate (0.050 g, 0.008 mmol). The reaction mixture was stirredovernight. The reaction mixture was diluted with 50 mL water and 50 mL10% methanol in dichloromethane. The layers were shaken and separatedand the organic phase was dried over magnesium sulfate and concentratedunder reduced pressure to give the desired product as a clear colorlessoil (0.029 g, 0.15 mmol). APCI (NEG.) m/z: 191.1 (M−H)−. ¹H NMR (400MHz, Methanol-d₄) δ 7.83-7.79 (m, 1H), 7.79-7.77 (m, 1H), 7.39-7.37 (m,2H), 4.89-4.86 (m, 2H), 4.60-4.57 (m, 2H), 1.63 (s, 3H).

Intermediate 34.0: Preparation of3-(1-((benzyloxy)carbonyl)-3-fluoroazetidin-3-yl)benzoic Acid

Step 1: Preparation of benzyl3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxyazetidine-1-carboxylate

2-(3-Bromophenyl)-1,3-dioxolane (1 mL, 6.6 mmol) in dry THF (10 mL) at−78° C. was added 1.6 M n-butyl lithium in hexanes (4.6 mL, 7.3 mmol)dropwise. The reaction mixture was stirred at −78° C. for 15 min thenadded benzyl 3-oxoazetidine-1-carboxylate (1.356 g, 6.6 mmol). Thereaction mixture was allowed to warm slowly to room temperature andstirred for 3 days. The reaction mixture was diluted with 50 mL waterand 50 mL ethyl acetate. The layers were shaken and separated and theorganic phase was dried over magnesium sulfate, concentrated underreduced pressure, and purified by silica gel chromatography with agradient to 100% ethyl acetate/hexanes to give the desired product as aclear colorless oil (0.798 g, 2.2 mmol). APCI (POS.) m/z: 356.10 (M+H)+.M+H=356.10, Rt=1.743 min, 3M POS. ¹H NMR (400 MHz, dichloromethane-d₂) δ7.66-7.63 (m, 1H), 7.57-7.52 (m, 1H), 7.50-7.43 (m, 2H), 7.43-7.33 (m,5H), 5.81 (s, 1H), 5.17-5.14 (m, 2H), 4.40-4.35 (m, 2H), 4.30-4.22 (m,2H), 4.19-4.00 (m, 4H).

Step 2: Preparation of benzyl3-(3-(1,3-dioxolan-2-yl)phenyl)-3-fluoroazetidine-1-carboxylate

Benzyl 3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxyazetidine-1-carboxylate(0.598 g, 1.7 mmol) in dry dichloromethane (16 mL) at −78° C. was added(diethylamino)sulfur trifluoride (0.267 mL, 2.0 mmol) dropwise. Thereaction mixture was stirred at −78° C. for 1 hour. The reaction mixturewas diluted with 50 mL 1M sodium hydroxide in water and 50 mLdichloromethane. The layers were shaken and separated and the organicphase was dried over magnesium sulfate, concentrated under reducedpressure, and purified by silica gel chromatography with a gradient to40% ethyl acetate/hexanes to give the desired product as a clearcolorless oil (0.443 g, 1.2 mmol). APCI (POS.) m/z: 358.10 (M+H)+. ¹HNMR (400 MHz, dichloromethane-d₂) δ 7.62-7.59 (m, 1H), 7.54-7.46 (m,3H), 7.44-7.33 (m, 5H), 5.82 (s, 1H), 5.19-5.15 (m, 2H), 4.55-4.45 (m,2H), 4.45-4.35 (m, 2H), 4.19-4.10 (m, 2H), 4.10-4.01 (m, 2H).

Step 3: Preparation of benzyl3-fluoro-3-(3-formylphenyl)azetidine-1-carboxylate

Benzyl 3-(3-(1,3-dioxolan-2-yl)phenyl)-3-fluoroazetidine-1-carboxylate(0.443 g, 1.2 mmol) in dichloromethane (4 mL) was added trifluoroaceticacid (0.950 mL, 12 mmol). The reaction mixture was stirred overnight.The sample was concentrated under reduced pressure and purified bysilica gel chromatography with a gradient to 30% ethyl acetate/hexanesto give the desired product as a clear colorless oil (0.389 g, 1.2mmol). APCI (POS.) m/z: 314.20 (M+H)+. ¹H NMR (400 MHz,dichloromethane-d₂) δ 10.08 (s, 1H), 8.03-8.01 (m, 1H), 7.95-7.92 (m,1H), 7.81-7.77 (m, 1H), 7.70-7.64 (m, 1H), 7.45-7.34 (m, 5H), 5.18 (s,2H), 4.60-4.50 (m, 2H), 4.46-4.36 (m, 2H).

Step 4: Preparation of3-(1-((benzyloxy)carbonyl)-3-fluoroazetidin-3-yl)benzoic Acid

Benzyl 3-fluoro-3-(3-formylphenyl)azetidine-1-carboxylate (0.445 g, 1.4mmol) and sodium periodate (1.519 g, 7.1 mmol) in chloroform (6 mL),acetonitrile (6 mL), and water (9 mL) was added ruthenium(III)trichloride monohydrate (0.015 g, 0.071 mmol). The reaction mixture wasstirred overnight. The reaction mixture was diluted with 50 mL water and50 mL 10% methanol in dichloromethane. The layers were shaken andseparated and the organic phase was dried over magnesium sulfate andconcentrated under reduced pressure to give the desired product as aclear red oil (0.403 g, 1.2 mmol). APCI (POS.) m/z: 330.1 (M+H)+. ¹H NMR(400 MHz, dichloromethane-d₂) δ 8.28-8.22 (m, 1H), 8.18-8.12 (m, 1H),7.84-7.75 (m, 1H), 7.65-7.58 (m, 1H), 7.45-7.34 (m, 5H), 5.19 (s, 2H),4.60-4.49 (m, 2H), 4.48-4.38 (m, 2H).

Intermediate 35.0: Preparation of 3-(3-fluorooxetan-3-yl)benzoic Acid

Step 1: Preparation of 3-(3-fluorooxetan-3-yl)benzaldehyde

3-Bromobenzaldehyde diethyl acetal (1 mL, 4.9 mmol) in dry THF (10 mL)at −78° C. was added 1.6M n-butyl lithium in hexanes (3.4 mL, 5.4 mmol)dropwise. The reaction mixture was stirred at −78° C. for fifteenminutes then added oxetan-3-one (0.353 g, 4.9 mmol) dropwise. Thereaction mixture was stirred at −78° C. for thirty minutes. The reactionmixture was diluted with 50 mL saturated ammonium chloride solution and50 mL ethyl acetate. The layers were shaken and separated and theorganic phase was dried over magnesium sulfate, concentrated underreduced pressure to give the desired product, and purified by silica gelchromatography with a gradient to 50% ethyl acetate/hexanes. The crudemixture was dissolved in dry dichloromethane (10 mL), cooled to −78° C.,and added diethylaminosulfur trifluoride (0.16 mL, 1.1 mmol) dropwise.The reaction mixture was stirred at −78° C. for thirty minutes. Thereaction mixture was warmed to room temperature. The reaction mixturewas diluted with 50 mL 1M sodium hydroxide and 50 mL ethyl acetate. Thelayers were shaken and separated and the organic phase was dried overmagnesium sulfate, concentrated under reduced pressure, and purified bysilica gel chromatography with a gradient to 30% ethyl acetate/hexanesto give the desired product as a clear colorless oil (0.051 g, 0.28mmol). ¹H NMR (400 MHz, dichloromethane-d₂) δ 10.10 (s, 1H), 8.13-8.10(m, 1H), 7.96-7.92 (m, 1H), 7.92-7.88 (m, 1H), 7.72-7.66 (m, 1H), 5.20

Step 2: Preparation of 3-(3-fluorooxetan-3-yl)benzoic acid, Intermediate35.0

3-(3-Fluorooxetan-3-yl)benzaldehyde (0.051 g, 0.28 mmol) in chloroform(1 mL), acetonitrile (1 mL), and water (1.5 mL) was added sodiumperiodate (0.304 g, 1.4 mmol) followed by ruthenium(III) trichloridemonohydrate (0.003 g, 0.014 mmol). The reaction mixture was stirredovernight. The reaction mixture was diluted with 50 mL water and 50 mLdichloromethane. The layers were shaken and separated and the organicphase was dried over magnesium sulfate and concentrated under reducedpressure to give the desired product as a white solid (0.050 g, 0.26mmol). ¹H NMR (400 MHz, Methanol-d₄) δ 8.25-8.23 (m, 1H), 8.10-8.05 (m,1H), 7.85-7.81 (m, 1H), 7.63-7.58 (m, 1H), 5.15-5.06 (m, 2H), 5.00-4.91(m, 2H).

Intermediate 36.0: Preparation of3-(1-((benzyloxy)carbonyl)-3-hydroxyazetidin-3-yl)benzoic Acid

Step 1: Preparation of benzyl3-(3-formylphenyl)-3-hydroxyazetidine-1-carboxylate

Benzyl 3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxyazetidine-1-carboxylate(0.199 g, 0.56 mmol) in dichloromethane (2 mL) was added trifluoroaceticacid (0.430 mL, 5.6 mmol). The reaction mixture was stirred overnight.The sample was concentrated under reduced pressure and purified bysilica gel chromatography with a gradient to 40% ethyl acetate/hexanesto give the desired product as a clear colorless oil (0.144 g, 0.46mmol). APCI (POS.) m/z: 312.10 (M+H)+. ¹H NMR (400 MHz,dichloromethane-d₂) δ 10.06 (s, 1H), 8.10-8.06 (m, 1H), 7.89-7.82 (m,2H), 7.65-7.60 (m, 1H), 7.42-7.32 (m, 5H), 5.15 (s, 2H), 4.39-4.28 (m,4H).

Step 2: Preparation of3-(1-((benzyloxy)carbonyl)-3-hydroxyazetidin-3-yl)benzoic acid,Intermediate 36.0

Benzyl 3-(3-formylphenyl)-3-hydroxyazetidine-1-carboxylate (0.144 g,0.46 mmol) and sodium periodate (0.495 g, 2.3 mmol) in chloroform (2mL), acetonitrile (2 mL), and water (3 mL) was added ruthenium(III)trichloride monohydrate (0.005 g, 0.023 mmol). The reaction mixture wasstirred overnight. The reaction mixture was diluted with 50 mL water and50 mL 10% methanol in dichloromethane. The layers were shaken andseparated and the organic phase was dried over magnesium sulfate andconcentrated under reduced pressure to give the desired product was aslightly yellow solid (0.105 g, 0.32 mmol). APCI (POS.) m/z: 328.10(M+H)+. ¹H NMR (400 MHz, dichloromethane-d₂) δ 8.17-8.13 (m, 1H),7.96-7.91 (m, 1H), 7.70-7.65 (m, 1H), 7.44-7.39 (m, 1H), 7.30-7.18 (m,5H), 5.02 (s, 2H), 4.28-4.23 (m, 2H), 4.21-4.16 (m, 2H).

Intermediate 37.0: Preparation of(1S,3s)-3-((R)-amino(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)cyclobutan-1-ol

Step 1: Preparation of(1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutane-1-carbaldehyde

To a solution of((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methanol (2.5 g,11.6 mmol) in DCM (30 mL) at 0 C was added Dess-Martin periodinane (7.35g, 17.3 mmol). The reaction was stirred for 15 mins at 0 C and then thesolution was warmed to rt. The reaction was monitored by TLC analysis.After the completion of the reaction, the reaction was cooled to 0 C andthen quenched with 2:1 sodium thiosulfate-sodium bicabonate solution.The reaction was stirred until the phases became clear. The aq. layerwas extracted once with DCM and the combined organic layer was dried,filtered, and concentrated to provide the product as a colorless oil(1.24 g, 5.78 mmol). ¹H NMR (DMSO-d₆) δ: 9.55 (d, J=2.5 Hz, 1H), 4.23(tt, J=7.9, 6.8 Hz, 1H), 2.65 (ttd, J=9.9, 7.6, 2.5 Hz, 1H), 2.37-2.29(m, 2H), 1.99-1.92 (m, 2H), 0.82 (s, 11H), 0.00 (s, 7H).

Step 2: Preparation of(S)—N—((Z)-((1s,3R)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methylene)-2-methylpropane-2-sulfinamide

A 100 mL round bottom flask was charged with(1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutane-1-carbaldehyde (1.85g, 8.63 mmol) and diluted with 1,2-dichloroethane (25 mL). To thatsolution was added (S)-(−)-2-methyl-2-propane-sulfinamide (1.05 g, 8.63mmol) and copper(II) sulfate, anhydrous (2 eq). The flask was fittedwith a findenser and heated to 55° C. After 24 hours, LCMS showed peakcontaining a mass consistent with the desired product. The roomtemperature solution was filtered through a pad of Celite andconcentrated under reduced pressure. The material was left of the highvacuum overnight to provide product as a vicious green oil (2.45 g, 7.71mmol). APCI (POS.) m/z: 318.20 (M+H)+. ¹H NMR (DMSO-d₆) δ: 7.92 (d,J=4.6 Hz, 1H), 4.24 (tt, J=8.0, 6.8 Hz, 1H), 2.95-2.77 (m, 1H),2.47-2.41 (m, 2H), 2.05-1.74 (m, 2H), 1.08 (s, 9H), 0.82 (s, 9H), 0.00(s, 7H).

Step 3: Preparation of(S)—N—((R)-((1s,3S)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide

To a 100 mL oven-dried 3 necked round bottom flask under nitrogen wasadded 1-bromo-2,5-difluoro-4-(trifluoromethyl)benzene (1.09 g, 3.45mmol) in anhydrous THF (15 mL). The resulting solution was cooled to −70C (internal temperature) with an acetone dry-ice bath.Isopropylmagnesium chloride lithium chloride complex (2.79 mL, 3.62mmol, 1.3 M) was then added dropwise while maintaining the internalreaction temperature between −65 C and −70 C. The resulting solution wasstirred at −70 C for 30 minutes, and then(S)—N—((Z)-((1s,3R)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methylene)-2-methylpropane-2-sulfinamidein 5 mL THF was added dropwise while maintaining the internaltemperature between −65 and −70 C. The resulting solution was stirred atthe same temperature for 120 minutes, and then the dry-ice was removedfrom the cooling bath and the reaction was allowed to warm to 0 C over30 minutes and at rt overnight (no reaction observed at 0 C—reactionproceeded at rt). It was then quenched with 30 ml saturated ammoniumchloride (aqueous) and then diluted with 40 mL ethyl acetate and 40 mLwater. The layers were shaken and separated and the organic phase waswashed with brine, dried over sodium sulfate and concentrated to a crudesticky solid which was purified with silica gel using a gradient from 0to 20% ethyl acetate/hexanes, providing the desired product as a whitefoam (1.06 g, 1.91 mmol, 2:1 mixture of diastereomers). APCI (POS.) m/z:500.20 (M+H)+. ¹H NMR (DMSO-d₆) δ: 7.82-7.60 (m, 4H), 5.77-5.61 (m, 2H),4.46 (t, J=8.4 Hz, 2H), 4.12-4.02 (m, 2H), 2.43 (ddt, J=12.1, 10.5, 6.1Hz, 2H), 2.17 (ddd, J=17.1, 9.8, 7.6 Hz, 2H), 2.11-2.01 (m, 2H),1.83-1.67 (m, 2H), 1.64-1.46 (m, 2H), 1.06 (s, 18H), 0.84 (d, J=2.1 Hz,18H), 0.00 (s, 12H).

Step 4: Preparation of(1S,3s)-3-((R)-amino(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)cyclobutan-1-ol,(Intermediate 37.0)

To a solution of (S)—N—((R)-((1s,3S)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide(0.95 g, 1.90 mmol) in 15 mL of methanol at 0° C. in an ice bath underargon was added 4M HCl in dioxane (1.42 mL, 5.70 mmol) dropwise andstirred for 5 minutes. Then the reaction mixture was stirred at 0 C for30 mins and warmed to RT and stirred for 30 minutes while continuouslymonitoring with TLC analysis. The reaction was deemed to be completeafter 30 minutes (LCMS analysis). After the reaction was completed, thereaction was quenched by adding triethylamine (10 mL). The resultingmixture was concentrated under reduced pressure, and the remaining whitesolid was partitioned between saturated sodium bicarbonate (30 mL) andDCM (30 mL). The layers were separated and the aqueous phase wasextracted with additional DCM (30 mL). The organic layers were combined,dried over sodium sulfate, filtered and concentrated under vacuum,providing the desired product as a viscous oil (0.51 g, 1.81 mmol). APCI(POS.) m/z: 282.20 (M+H)+. ¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (dt, J=9.9,3.7 Hz, 2H), 5.08-4.87 (m, 1H), 4.11-4.00 (m, 1H), 3.86 (d, J=6.3 Hz,1H), 2.32-2.23 (m, 1H), 2.17 (d, J=40.5 Hz, 2H), 2.04-1.93 (m, 1H),1.91-1.78 (m, 1H), 1.61 (ddt, J=29.0, 10.0, 8.2 Hz, 2H).

The compounds set forth in the following table were synthesizedfollowing the procedure outlined above using known starting materialreplacements as described.

TABLE 12 Intermediate Reagents Structure, Name and Data Intermediate37.0 ((1S,3S)-3-((tert- butyldimethyl- silyl)oxy)cyclo- butyl)methanol

(1S,3s)-3-((R)-amino(2,5- difluoro-4-(trifluoro-methyl)phenyl)methyl)cyclo- butan-1-ol LCMS-ESI (POS.) m/z: 282.20 (M +H)+ Intermediate 37.1 ((1R,3R)-3-((tert- butyldimethyl- silyl)oxy)cyclo-butyl)methanol

(1R,3r)-3-((R)-amino(2,5- difluoro-4-(trifluoro-methyl)phenyl)methyl)cyclo- butan-1-ol LCMS-ESI (POS.) m/z: 282.20 (M +H)+

General Procedures

Route A:

Example Route A: Example 758

Step 1: A 40-mL pressure release vial was charged with(R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)pyrrolidine-2-carboxylicacid (Intermediate 1, 150 mg, 0.41 mmol) and DMF (2.0 mL). To thatsolution was added DIPEA (0.20 mL, 1.15 mmol), benzylamine (0.10 mL,0.92 mmol) and TBTU (195 mg, 0.61 mmol), respectively. The vial wassealed and allowed to stir at room temperature for 30 min. The crudematerial was filtered through a 0.45 μm syringe tip filter and purifiedby preparative HPLC (XSelect CSH Prep C18 10 μm ODB 19×100 mm, A: water0.1% formic acid B: acetonitrile 0.1% formic acid, Gradient: 25% (2min), 25-70% (12 min), Flow Rate: 40 mL/min, monitored @ 215 nm) to give(R)—N-benzyl-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)pyrrolidine-2-carboxamide(Example 758, 145 mg) as a fluffy white solid. ¹H NMR (500 MHz,chloroform-d) δ ppm 7.18-7.38 (m, 5H), 4.62 (br d, J=5.97 Hz, 1H),4.40-4.50 (m, 2H), 4.10-4.17 (m, 4H), 3.78 (br d, J=12.07 Hz, 2H),3.57-3.66 (m, 2H), 3.42-3.49 (m, 1H), 2.97-3.02 (m, 1H), 2.69-2.82 (m,2H), 2.44-2.49 (m, 1H), 2.18-2.26 (m, 1H), 1.49-2.14 (m, 7H). LCMS-ESI(POS.) m/z: 460.2 (M+H)+.

In a second illustrative example the compound of Example 403 is preparedby the process of the general scheme for Route A:

Example 402: Preparation of(2R,4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide

Step 1: Preparation of (2R,4S)-tert-butyl2-(((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate.(R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methanaminehydrochloride (Intermediate 9.5, 1.4 g, 5.14 mmol), TBTU (1.7 g, 5.14mmol), and (2R,4S)-1-Boc-4-fluoropyrrolidine-2-carboxylic acid (1.2 g,5.14 mmol) were added to a 100-mL round-bottom flask. DCM (26 mL) wasadded and the reaction was stirred at rt as DIPEA (2.70 mL, 15.43 mmol)was introduced in a single portion. The reaction was stirred at rt for30 min. The crude solution was then carried on directly to thesubsequent step. LCMS (POS.) m/z: 471.0 (M+Na)+.

Step 2: Preparation of(2R,4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide

Crude (2R,4S)-tert-butyl2-(((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate(2.31 g, 5.14 mmol) dissolved in DCM (25.7 mL) from the previous stepwas stirred at rt. TFA (7.66 mL, 103 mmol) was added dropwise and thereaction was stirred at rt for 1 h. The volatiles were removed underreduced pressure and the product was used directly without purification.LCMS (POS.) m/z: 349.2 (M+H)+.

Step 3: Preparation of(2R,4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide

A 50 mL round-bottom flask was charged with(2R,4S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoropyrrolidine-2-carboxamide(1.69 g, 5.00 mmol), DIPEA (2.6 mL, 15.0 mmol),3-(methylsulfonyl)benzoic acid (1.00 g, 5.00 mmol), TBTU (1.69 g, 5.25mmol), and DMF (10.0 mL). The reaction was stirred for 1 h and thenpurified directly by preparative HPLC (XSelect CSH Prep C18 10 μm ODB19×100 mm, A: water 0.1% TFA B: acetontrile 0.1% TFA, gradient: 25% (2min), 25-70% (12 min), flow Rate: 40 mL/min, monitored @ 215 nm) to givethe title compound as a white solid (1.78 g). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 8.57-8.92 (m, 1H), 7.46-8.11 (m, 7H), 5.17-5.42 (m, 1H), 4.56-4.76(m, 2H), 3.49-4.25 (m, 6H), 1.81-2.04 (m, 1H), 0.80-1.29 (m, 1H),−0.23-0.66 (m, 4H). LCMS (POS.) m/z: 531.0 (M+H)+.

In a third illustrative example the compound of Example 365 is preparedby the process of the general scheme for Route A:

Example 364: Preparation of(R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide Step 1: Preparation of (R)-tert-butyl2-(((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate

A 50 mL round bottom flask with magnetic stir bar was charged with(R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methanaminehydrochloride (Intermediate 9.5, 940 mg, 3.49 mmol), DIPEA (1.82 mL,10.5 mmol), N-(tert-butoxycarbonyl)-D-proline (750 mg, 3.49 mmol), andTBTU (1.12 g, 3.49 mmol) in DCM (7.0 mL). The reaction was stirred at rtfor 4 h and then washed once with 1N HCl and then once with brine. Theorganics were separated, dried over sodium sulfate, and concentratedunder reduced pressure. The crude product was adsorbed onto silica geland purified by column chromatography (silica gel, 230-400 mesh) using0-100% EtOAc/hexanes to give the title compound as a white solid (1.45g, 3.37 mmol). ¹H NMR (500 MHz, chloroform-d) δ ppm 7.42-7.53 (m, 1H),7.36-7.42 (m, 1H), 7.31 (br d, J=9.86 Hz, 1H), 4.12-4.73 (m, 2H),3.20-3.71 (m, 2H), 1.75-2.55 (m, 4H), 1.10-1.77 (m, 11H), 0.48-0.77 (m,2H), 0.26-0.48 (m, 2H). LCMS (POS.) m/z: 453.2 (M+Na)+.

Step 2: Preparation of(R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)pyrrolidine-2-carboxamidehydrochloride

A 100 mL round-bottom flask with magnetic stir bar was charged with(R)-tert-butyl2-(((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate(1.45 g, 3.37 mmol), DCM (15 mL) and HCl (4M in 1,4-dioxane, 12.63 mL,50.5 mmol). The reaction was stirred at rt for 2 h. The volatiles werethen removed under reduced pressure to give desired product as a whitesolid (1.20 g). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.75-10.22 (m, 1H), 9.46(br d, J=6.75 Hz, 1H), 8.47 (br d, J=2.85 Hz, 1H), 7.69-7.78 (m, 1H),7.59-7.69 (m, 2H), 4.43-4.56 (m, 1H), 4.25 (br t, J=7.79 Hz, 1H), 3.33(s, 1H), 3.16 (br t, J=7.14 Hz, 2H), 2.25-2.42 (m, 1H), 1.72-1.96 (m,2H), 1.61-1.72 (m, 1H), 1.19-1.37 (m, 1H), 0.56-0.68 (m, 1H), 0.50 (tt,J=8.79, 4.57 Hz, 1H), 0.41 (dq, J=9.47, 4.80 Hz, 1H), 0.34 (dt, J=9.54,4.70 Hz, 1H). LCMS (POS.) m/z: 331.2 (M+H)+.

Step 3: Preparation of(R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide

3-(methylsulfonyl)benzoic acid (1.15 g, 5.76 mmol), TBTU (1.85 g, 5.76mmol), and(R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)pyrrolidine-2-carboxamide(1.59 g, 4.8 mmol) were suspended in DCM (24 mL). DIPEA (2.5 mL, 14.40mmol) was added dropwise and the reaction was stirred at rt for 1 h. Thereaction mixture was washed once with saturated sodium bicarbonatesolution, dried over sodium sulfate, filtered, and concentrated. Thecrude product was purified directly by preparative HPLC (XSelect CSHPrep C18 10 μm ODB 19×100 mm, A: water 0.1% TFA B: acetontrile 0.1% TFA,gradient: 25% (2 min), 25-70% (12 min), flow Rate: 40 mL/min, monitored@ 215 nm) to give the title compound as a white solid (1.58 g, 3.08mmol). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.49-8.78 (m, 1H), 7.51-8.07 (m,7H), 4.18-4.65 (m, 2H), 3.38-3.69 (m, 2H), 3.25-3.31 (m, 3H), 2.13-2.29(m, 1H), 1.64-1.92 (m, 3H), 0.88-1.29 (m, 1H), −0.06-0.66 (m, 4H). LCMS(POS.) m/z: 513.2 (M+H)+.

Route B:

Example Route B: Example 346

Step 1: 3-(chlorosulfonyl)benzoyl chloride (0.091 mL, 0.379 mmol) wasdissolved in DCM (1.0 mL) at 0° C. DIPEA (0.165 mL, 0.948 mmol) wasadded followed by(R)—N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide (Intermediate28.0, 0.06 g, 0.190 mmol) dropwise over 15 minutes. Sarcosine methylester hydrochloride, DMAP (0.023 g, 0.190 mmol), and DIPEA (0.165 mL,0.948 mmol) were then added and the reaction was warmed to rt for 60min. The crude material was filtered through a 0.45 μm syringe tipfilter and purified by preparative HPLC (XSelect CSH Prep C18 10 μm ODB19×100 mm, A: water 0.1% formic acid B: acetonitrile 0.1% formic acid,gradient: 25% (2 min), 25-70% (12 min), flow rate: 40 mL/min, monitored@ 215 nm) to give methyl(R)-2-(N-methyl-3-(2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)phenylsulfonamido)acetate,Example 346 (13 mg) as a fluffy white solid. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.27-7.92 (m, 9H), 7.24-7.25 (m, 1H), 4.62-4.76 (m,1H), 4.38-4.54 (m, 2H), 3.92-4.01 (m, 2H), 3.45-3.59 (m, 4H), 3.30-3.43(m, 1H), 2.74-2.90 (m, 3H), 2.35-2.47 (m, 1H), 1.98-2.12 (m, 2H),1.96-2.13 (m, 2H), 1.73-1.89 (m, 1H). LCMS-ESI (POS.) m/z: 542.2 (M+H)+.

Route C:

Example Route C: Example 19

Step 1: A 40-mL pressure release vial was charged with(R)-4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (500 mg, 2.16mmol) and dissolved in DCM (10 mL). To that stirring solution at rt wasadded DIPEA (0.94 mL, 5.41 mmol),(R)-1-(4-(trifluoromethyl)phenyl)ethanamine (532 mg, 2.81 mmol) and TBTU(764 mg, 2.38 mmol). After 2 hours at rt, the crude material was loadeddirectly onto a silica gel column, and purified by flash chromatography(50 g Biotage eluting with 0-50% ethyl acetate:ethanol 3:1 (v/v) inheptane) to provide tert-butyl(R)-3-(((R)-1-(4-(trifluoromethyl)phenyl)ethyl)carbamyl)morpline-4-carbxyate(829 mg, 2.06 mmol) as an amorphous white foam. LCMS-ESI (POS.) m/z:425.2 (M+Na)+.

Step 2: A 40-mL pressure release vial was charged with tert-butyl(R)-3-(((R)-1-(4-(trifluoromethyl)phenyl)ethyl)carbamoyl)morpholine-4-carboxylate(829 mg, 2.06 mmol) and dissolved in dichloromethane (10 mL). To thatsolution was added 4.0M HCl in dioxane (2.06 mL, 8.24 mmol). The vialwas sealed and allowed to stir at rt for 19 h. The white precipitate wascollected by filtration and washed with heptane to give(R)—N—((R)-1-(4-(trifluoromethyl)phenyl)ethyl) morpholine-3-carboxamidehydrochloride (635 mg) as an analytically pure white solid. LCMS-ESI(POS.) m/z: 303.2 (M+H)+.

Step 3: A 40-mL pressure release vial was charged with(R)—N—((R)-1-(4-(trifluoromethyl)phenyl)ethyl)morpholine-3-carboxamidehydrochloride (150 mg, 0.443 mmol) and DMF (2.5 mL). To that stirringsolution at rt was added DIPEA (0.50 mL, 2.86 mmol),3-((3-cyanoazetidin-1-yl)sulfonyl)benzoic acid (Intermediate 3.1, 130mg, 0.487 mmol) and finally TBTU (213 mg, 0.664 mmol). The vial wassealed and allowed to stir for 24 h at rt. The reaction was diluted witha small amount of water and filtered through a 0.45 μm syringe tipfilter and purified by preparative HPLC (XSelect CSH Prep C18 10 μm ODB19×100 mm, A: water 0.1% TFA B: acetonitrile 0.1% TFA, gradient: 25% (2min), 25-70% (12 min), flow Rate: 40 mL/min, monitored @215 nm) to give(R)-4-(3-((3-cyanoazetidin-1-yl)sulfonyl)benzoyl)-N—((R)-1-(4-(trifluoromethyl)phenyl)ethyl)morpholine-3-carboxamide,also referred to as(3R)-4-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-3-morpholinecarboxamideExample 19 (221.2 mg) as an off-white solid. ¹H NMR (500 MHz, DMSO-d₆) δppm 8.52-8.73 (m, 1H), 7.95 (br s, 1H), 7.75-7.88 (m, 3H), 7.70 (br d,J=8.04 Hz, 2H), 7.54 (br d, J=6.62 Hz, 2H), 5.05 (br s, 1H), 4.20-4.44(m, 2H), 3.52-4.07 (m, 8H), 3.10-3.49 (m, 2H), 1.32-1.48 (m, 3H).LCMS-ESI (POS.) m/z: 551.2 (M+H)+.

Second illustrative example prepared by the general scheme for Route C:

Example 218: Preparation of(1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(5-(methylsulfonyl)nicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(which compound is also referred to herein as(1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide)Step 1: Preparation of(S,E)-N-(4-chloro-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide

(S)-(−)-2-methyl-2-propanesulfinamide (18.88 g, 156 mmol and copper(II)sulfate (9.42 g, 212 mmol) were suspended in 1,2-dichloroethane (283 mLat rt. 4-Chloro-2,5-difluorobenzaldehyde (25.00 g, 142 mmol) was addedand the reaction was heated to 55° C. for 12 h. The turbid yellowsolution was filtered through celite and silica. The filter cake waswashed with 1,2-dichloroethane (250 mL) and then the filtrate wasconcentrated to give a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.61 (s, 1H), 8.02-7.91 (m, 2H), 1.20 (s, 9H). LCMS (POS.) m/z:280.0 (M+H)+.

Step 2: Preparation of(S)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide

(S,E)-N-(4-chloro-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide(4.0 g, 14.3 mmol) was dissolved in DCM (72 mL) and cooled to −78° C.Cyclopropylmagnesium bromide (1M in 2-MeTHF, 21.5 mL, 21.5 mmol, 1.5equiv) was then added dropwise and the reaction was allowed to slowlywarm to rt and stirred an additional 2 hours. The reaction was quenchedby addition of saturated aqueous ammonium chloride solution with rapidstirring. The organics were separated, and the aqueous layer was washedtwice with DCM (2×50 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated. The crude product was purified bycolumn chromatography (silica gel, 230-400 mesh) using 10-70% EtOAc inhexanes to give the title compound as a viscous yellow oil. Thestereochemistry was assigned based on literature precedent (Ellman, J.A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984). ¹H NMR(500 MHz, chloroform-d) δ ppm 7.20-7.26 (m, 1H), 7.10-7.20 (m, 1H), 3.90(d, J=9.34 Hz, 1 H), 3.59 (br s, 1H), 1.23 (s, 8H), 0.67-0.77 (m, 1H),0.44-0.62 (m, 3H). LCMS-ESI (POS.) m/z: 322.2 (M+H)+.

Step 3. Preparation of(R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methanamine hydrochloride(Intermediate 9.2)

(S)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide(3.8 g, 12.0 mmol) was dissolved in methanol (14.0 mL) followed byaddition of HCl (4M in dioxane, 6 mL, 24.0 mmol). The solution wasstirred 2 h and then the volatiles were removed under reduced pressure.The crude solid was slurried in EtOAc and then the solids were collectedby filtration to give(R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methanamine hydrochloride(Intermediate 9.2, 2.6 g) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 8.88 (br s, 3H), 7.99 (dd, J=9.85, 6.32 Hz, 1H), 7.77 (dd, J=9.43,6.22 Hz, 1H), 3.79 (br d, J=8.50 Hz, 1H), 1.35-1.44 (m, 1H), 0.64-0.72(m, 2H), 0.48-0.57 (m, 1H), 0.28-0.35 (m, 1H). LCMS (POS.) m/z: 201.2(M-NH₂)+.

Step 4. Preparation of 1R,3R,5R)-tert-butyl3-(((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A 20 mL vial with a stir bar was charged with(1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (100 mg, 0.440 mmol) TBTU (141 mg, 0.440 mmol)(R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methanamine hydrochloride(Intermediate 9.2, 112 mg, 0.440 mmol), DIPEA (0.129 mL, 0.88 mmol) andDCM (1.1 mL). The reaction was stirred at 25° C. for 2 h, concentrated,and then purified by column chromatography (silica gel, 230-400 mesh)using 0-50% EtOAc in hexanes to give the title compound as a white solid(178 mg). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.22-8.72 (m, 1H), 7.25-7.70(m, 2H), 4.06-4.56 (m, 2H), 3.36 (br d, J=3.89 Hz, 1H), 1.57-1.80 (m,1H), 1.12-1.56 (m, 13H), 0.74-0.94 (m, 2H), 0.39-0.70 (m, 3H), 0.22-0.39(m, 2H). LCMS (POS.) m/z: 465.2 (M+Na)+.

Step 5. Preparation of(1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamidehydrochloride (Intermediate 28.4)

A 100 mL round bottom flask with magnetic stir bar was charged with(1R,3R,5R)-tert-butyl 3-(((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(1.9 g, 4.4 mmol), HCl (4M in dioxane, 2.2 mL, 8.9 mmol) and DCM (11.0mL). After stirring at rt for 2 h, the volatiles were removed underreduced pressure to produce a white solid (Intermediate 28.4, 1.60 g).¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.55 (br s, 1H) 9.33 (d, J=7.27 Hz, 1H)8.74 (br s, 1H) 7.64 (t, J=7.56 Hz, 1H) 7.60 (t, J=7.76 Hz, 1H) 4.56(dd, J=10.90, 3.11 Hz, 1H) 4.35-4.44 (m, 1H) 3.56 (s, 1H) 3.23-3.30 (m,1H) 2.47-2.53 (m, 3H) 2.00 (dd, J=13.75, 3.11 Hz, 1H) 1.67-1.76 (m, 1H)1.19-1.30 (m, 2H) 0.69-0.87 (m, 2H) 0.44-0.61 (m, 3H) 0.25-0.42 (m, 2H).LCMS (POS.) m/z: 327.2 (M+H)+.

Step 6. Preparation of (1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(5-(methylsulfonyl)nicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 218)

5-(methylsulfonyl)-3-pyridinecarboxylic acid (2.28 g, 11.32 mmol), TBTU(3.82 g, 11.89 mmol), and(1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamidehydrochloride (Intermediate 28.4, 3.7 g, 11.32 mmol) were suspended inDCM (56.6 mL) at rt. DIPEA (5.92 mL, 34.0 mmol) was added and thereaction was stirred at rt for 30 minutes. The reaction was diluted withDCM and washed once with 1N HCl, dried over sodium sulfate, filtered andconcentrated. The crude material was purified by preparative HPLC(XSelect CSH Prep C18 10 μm ODB 19×100 mm, A: water 0.1% TFA B:acetontrile 0.1% TFA, gradient: 25% (2 min), 25-70% (12 min), flow Rate:40 mL/min, monitored @ 215 nm) to give(1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(5-(methylsulfonyl)nicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamideas a white solid (Example 218, 2.77 g).

Third Illustrative Example Prepared by the General Scheme for Route C:

Example 314: Preparation of(1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(2-(methylsulfonyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide,also referred to as(1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide

Preparation of(1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(2-(methylsulfonyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide.TBTU (78 mg, 0.24 mmol),(1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Intermediate 28.4, 72 mg, 0.22 mmol), and2-(methylsulfonyl)isonicotinic acid (49 mg, 0.24 mmol) were dissolved inDMF (1.1 mL) at rt. DIPEA (0.12 mL, 0.660 mmol) was added and thereaction was stirred at rt for 2 h. The reaction mixture was thenpurified preparative HPLC (XSelect CSH Prep C18 10 μm ODB 19×100 mm, A:water 0.1% TFA B: acetontrile 0.1% TFA, gradient: 25% (2 min), 25-70%(12 min), flow Rate: 40 mL/min, monitored @ 215 nm) to give a whitesolid (Example 314, 48.1 mg).

In a Fourth Illustrative Example the Compound of Example 214 is Preparedby the Process of the General Scheme for Route C:

Example 214: Preparation of(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(5-(methylsulfonyl)nicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(which Compound is Also Referred to Herein as(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide)

Step 1. Preparation of 2,5-difluoro-4-(trifluoromethyl)benzaldehyde. Toa solution of 1-bromo-2,5-difluoro-4-(trifluoromethyl)benzene (130 g,498 mmol, Oakwood, Inc.) in THF (1.3 L) was added isopropylmagnesiumchloride (2M solution in THF, 274 mL, 548 mmol) drop-wise under nitrogenatmosphere at −45° C. The reaction mixture was stirred at −45° C. for 30min and then DMF (174 mL, 2.24 mol) was slowly added and stirred for 20min. The reaction mixture was allowed to warm to 0° C. and quenched withsaturated aqueous NH₄Cl solution (500 mL), diluted with water (1.5 L),and extracted with EtOAc (3×2 L). The organic extracts were washed withbrine (2.0 L) and dried over Na₂SO₄, filtered, and concentrated underreduced pressure to give 2,5-difluoro-4-(trifluoromethyl)benzaldehyde(65 g) as a colorless oil. ¹H NMR (400 MHz, Chloroform-d): δ 10.38 (s,1H), 7.71 (dd, J=9.2, 5.2 Hz, 1H), 7.52 (dd, J=9.2, 5.2 Hz, 1H).

Step 2: Preparation of(S,E)-N-(2,5-difluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide

To a suspension of copper(II) sulfate (228 g, 1.43 mol) and(S)-(−)-2-methylpropane-2-sulfinamide (130 g, 1.07 mol) in1,2-dichloroethane (2.2 L) was added2,5-difluoro-4-(trifluoromethyl)benzaldehyde (150 g, 0.714 mol) at rt.The reaction was heated to 80° C. and stirred for 18 h. The mixture wasthen filtered through a pad of Celite and the filter cake was washedwith 1,2-dichloroethane (500 mL). The filtrate was concentrated underreduced pressure and purified by column chromatography (silica gel,60-120 mesh) eluting with 4-10% EtOAc in hexanes to provide(S,E)-N-(2,5-difluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide(195 g) as a brown viscous oil. ¹H NMR (400 MHz, Chloroform-d): 68.88(s, 1H), 7.85 (dd, J=9.6, 5.6 Hz, 1H), 7.47 (dd, J=9.2, 5.2 Hz, 1H),1.31 (s, 9H).

Step 3: Preparation of(S)—N—((S)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamideand(S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide

A solution of(S,E)-N-(2,5-difluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide(195 g, 622 mmol) in DCM (3.6 L) was cooled to −78° C.Cyclopropylmagnesium bromide (0.5M in THF, 1.87 L, 934 mmol) was thenadded dropwise over 1 h. The reaction mixture was stirred at −78° C. foran additional 1 h and then allowed to warm to rt over 2 h. The reactionmixture was quenched with saturated aqueous NH₄Cl solution (700 mL) andextracted with DCM (3×700 mL). The organic extracts were washed withwater (500 mL), brine (500 mL), dried over Na₂SO₄, and concentratedunder reduced pressure. The crude residue purified by columnchromatography (silica gel, 230-400 mesh) using 5-15% EtOAc in hexanes.The first eluting peak (minor) was assigned as(S)—N—((S)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide(16 g) based on literature precedent (see Ellman, J. A.; Owens, T. D.;Tang, T. P. Acc. Chem. Res. 2002, 35, 984) and collected as a brown oil.¹H NMR (400 MHz, DMSO-d₆): δ7.78-7.65 (m, 2H), 5.95 (d, J=8.0 Hz, 1H),3.87 (dd, J=8.0, 7.4 Hz, 1H), 1.27-1.20 (m, 1H), 1.12 (s, 9H), 0.65-0.60(m, 1H), 0.52-0.46 (m, 2H), 0.37-0.33 (m, 1H). LCMS-ESI (POS.) m/z:356.1 (M+H)+. The second eluting peak (major) was assigned as(R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide(95 g) based on literature precedent (Ellman, J. A.; Owens, T. D.; Tang,T. P. Acc. Chem. Res. 2002, 35, 984) and collected as a brown oil. ¹HNMR (400 MHz, DMSO-d₆): δ 7.78-7.70 (m, 2H), 5.73 (d, J=6.8 Hz, 1H),3.87 (dd, J=8.0, 6.8 Hz, 1H), 1.32-1.27 (m, 1H), 1.08 (s, 9H), 0.65-0.61(m, 1H), 0.52-0.46 (m, 2H), 0.37-0.33 (m, 1H). LCMS-ESI (POS.) m/z:356.2 (M+H)+.

Step 4: Preparation of(R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methanaminehydrochloride, Intermediate 8.0

To a solution of(S)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide(95 g, 268 mmol) in methanol (450 mL) was added HCl (4M in dioxane, 134mL, 535 mmol) at 0° C. and stirred at rt for 2 h. The reaction mixturewas concentrated under reduced pressure and azeotroped with DCM (500mL). The residual solid was triturated with diethyl ether (500 mL),collected by filtration, and dried under vacuum to give(R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methanaminehydrochloride (Intermediate 8.0, 73 g) as an off-white solid. ¹H NMR(400 MHz, DMSO-d₆): δ 9.10 (s, 3H), 8.19 (dd, J=10.8, 5.6 Hz, 1H), 7.88(dd, J=8.4, 6.4 Hz, 1H), 3.87 (d, J=8.8 Hz, 1H), 1.46-1.38 (m, 1H),0.78-0.68 (m, 2H), 0.57-0.53 (m, 1H), 0.39-0.33 (m, 1H). LCMS-ESI (POS.)m/z: 252.1 (M+H)+.

Step 5: Preparation of (1R,3R,5R)-tert-butyl3-(((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A 50 mL round-bottom flask was charged with TBTU (1.61 g, 5.0 mmol),DIPEA (2.6 mL, 15.0 mmol),(R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methanaminehydrochloride (Intermediate 8.0, 1.44 g, 5.00 mmol),(1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (1.14 g, 5.00 mmol), and DCM (12.5 mL). The reaction was stirredfor 20 min and then diluted with DCM and then washed 1N HCl, saturatedaqueous sodium bicarbonate, and brine. The organics were dried oversodium sulfate, filtered, and concentrated to give a viscous yellow oilthat was purified by column chromatography (silica gel, 230-400 mesh)using 0-50% EtOAc in hexanes to give the title compound as a white solid(2.01 g). ¹H NMR (500 MHz, DMSO-d₆): δ 8.52-8.76 (m, 1H) 7.66-7.78 (m,1H) 7.56-7.66 (m, 1H) 4.55 (br dd, J=10.90, 2.85 Hz, 1H) 4.31-4.46 (m,2H) 3.27-3.36 (m, 1H) 2.60 (td, J=12.46, 6.23 Hz, 1H) 1.80 (dd, J=13.36,2.72 Hz, 1H) 1.40-1.52 (m, 1H) 1.37 (s, 3H) 1.19-1.32 (m, 2H) 1.10 (s,5H) 0.94-1.07 (m, 1H) 0.79-0.94 (m, 1H) 0.19-0.64 (m, 5H). LCMS-ESI(POS.) m/z: 483.2 (M+Na)+.

Step 6: Preparation of(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamidemethanesulfonate

500 mL round-bottom flask equipped with magnetic stir bar, refluxcondenser and argon inlet was charged with (1R,3R,5R)-tert-butyl3-(((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(24.3 g, 52.8 mmol) and methyl tert-butyl ether (200 mL). The flask wasplaced into heating block and heated to 50° C. then methanesulfonic acid(5.14 mL, 79 mmol) was added dropwise via syringe within 5 min (slow gasevolution starts after addition of −1 mL). The mixture was stirred at50° C. until gas evolution stopped (˜2 h) at which point a white solidprecipitated. The mixture was allowed to reach rt and stirred overnightat rt. The white solid was filtered off and washed with 20 mL MTBE anddried to afford(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamidemethanesulfonate as a white solid (21.13 g, 46.3 mmol). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.46 (d, J=8.04 Hz, 1H) 7.67-7.76 (m, 2H) 4.32 (t, J=8.82Hz, 1H) 3.73-3.84 (m, 1H) 3.22 (br s, 1H) 2.79 (td, J=6.29, 2.72 Hz, 1H)1.92-2.06 (m, 2H) 1.35 (qd, J=8.52, 4.54 Hz, 1H) 1.18-1.29 (m, 1H)0.51-0.61 (m, 1H) 0.46 (tt, J=8.56, 4.41 Hz, 1H) 0.25-0.38 (m, 3H)−0.35-−0.24 (m, 1H). LCMS-ESI (POS.) m/z: 361.2 (M+H)+.

Step 7: Preparation of(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(5-(methylsulfonyl)nicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 214)

To a suspension of(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamidemethanesulfonate (11.19 g, 24.52 mmol) in isopropyl acetate (65.0 mL),5-(methylsulfonyl)nicotinic acid (4.93 g, 24.52 mmol) was added followedby DIPEA (12.85 mL, 73.5 mmol). The resulting mixture was stirred for 2min then 1-propanephosphonic acid cyclic anhydride (50 wt. % solution inEtOAc, 21.89 mL, 36.8 mmol) was added dropwise and the mixture wasstirred for 1 h at rt. The reaction was treated with HCl (2N, 36.8 mL,73.5 mmol) and stirred for 20 min at rt. The organic layer was separatedand washed with water and brine, filtered through celite andconcentrated to afford yellow oil. This oil was diluted with 10 mLi-PrOH and heated to 60° C. and stirred at rt for 30 min. Theprecipitated material was collected by filtration and washed with i-PrOH(˜15 mL) and dried to afford(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(5-(methylsulfonyl)nicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 214, 9.68 g)¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.83-9.24 (m, 2H),8.28-8.80 (m, 2H), 7.68-7.82 (m, 1H), 7.36-7.64 (m, 1H), 4.00-5.05 (m,2H), 3.34-3.41 (m, 4H), 2.56-2.76 (m, 1H), 1.53-1.79 (m, 2H), −0.28-1.24(m, 7H). LCMS-ESI (POS.) m/z: 544.2 (M+H)+.

In a fifth illustrative example the compound of Example 279 is preparedby the process of the general scheme for Route C:

Example 279: Preparation of(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-(methylsulfonyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide,Also Referred to Herein as(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamideStep 1: Preparation of (1R,3R,5R)-tert-butyl3-(((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

A 50 mL round-bottom flask was charged with TBTU (1.61 g, 5.0 mmol),DIPEA (2.6 mL, 15.0 mmol),(R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methanaminehydrochloride (Intermediate 8.0, 1.44 g, 5.00 mmol),(1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (1.14 g, 5.00 mmol), and DCM (12.5 mL). The reaction was stirredfor 20 min and then diluted with DCM and then washed 1N HCl, saturatedaqueous sodium bicarbonate, and brine. The organics were dried oversodium sulfate, filtered, and concentrated to give a viscous yellow oilthat was purified by column chromatography (silica gel, 230-400 mesh)using 0-50% EtOAc in hexanes to give the title compound as a white solid(2.01 g). 8.52-8.76 (m, 1H) 7.66-7.78 (m, 1H) 7.56-7.66 (m, 1H) 4.55 (brdd, J=10.90, 2.85 Hz, 1H) 4.31-4.46 (m, 2H) 3.27-3.36 (m, 1H) 2.60 (td,J=12.46, 6.23 Hz, 1H) 1.80 (dd, J=13.36, 2.72 Hz, 1H) 1.40-1.52 (m, 1H)1.37 (s, 3H) 1.19-1.32 (m, 2H) 1.10 (s, 5H) 0.94-1.07 (m, 1H) 0.79-0.94(m, 1H) 0.19-0.64 (m, 5H). LCMS (POS.) m/z: 483.2 (M+Na)+.

Step 2: Preparation of(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide

A 50 mL round-bottom flask was charged with (1R,3R,5R)-tert-butyl3-(((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2.01 g, 4.37 mmol) and DCM (8.8 mL) followed by addition of TFA (3.4mL, 43.7 mmol). The reaction was stirred for 2 h and then diluted with50 mL DCM. The excess acid was quenched by drop-wise addition ofsaturated sodium bicarbonate solution with rapid stirring. The layerswere separate and the aqueous fraction was washed twice with 50 mL DCM.The combined organics were dried over sodium sulfate, filtered, andconcentrated to give the desired product as a white solid (1.51 g, 4.2mmol). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.46 (d, J=8.04 Hz, 1H) 7.67-7.76(m, 2H) 4.32 (t, J=8.82 Hz, 1H) 3.73-3.84 (m, 1H) 3.22 (br s, 1H) 2.79(td, J=6.29, 2.72 Hz, 1H) 1.92-2.06 (m, 2H) 1.35 (qd, J=8.52, 4.54 Hz,1H) 1.18-1.29 (m, 1H) 0.51-0.61 (m, 1H) 0.46 (tt, J=8.56, 4.41 Hz, 1H)0.25-0.38 (m, 3H) −0.35-−0.24 (m, 1H). LCMS (POS.) m/z: 361.2 (M+H)+.

Step 3: Preparation of(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-(methylsulfonyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide

A 25 mL round-bottom flask was charged with(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(273 mg, 0.758 mmol), 2-(methylsulfonyl)isonicotinic acid (152 mg, 0.758mmol), TBTU (243 mg, 0.758 mmol), DIPEA (0.377 mL, 2.17 mmol), and DMF(3.6 mL). The reaction was stirred for 2.5 h. The reaction mixture waspurified directly by preparative HPLC (XSelect CSH Prep C18 10 μm ODB19×100 mm, A: water 0.1% TFA B: acetontrile 0.1% TFA, gradient: 25% (2min), 25-70% (12 min), flow Rate: 40 mL/min, monitored @ 215 nm) to givethe title compound (237.8 mg). ¹H NMR (500 MHz, DMSO-d₆) b ppm 8.94 (d,J=4.80 Hz, 1H), 8.75 (d, J=7.40 Hz, 1H), 7.83-8.27 (m, 2H), 7.69-7.81(m, 1H), 7.59 (dd, J=11.03, 5.45 Hz, 1H), 4.11-5.04 (m, 2H), 3.19-3.37(m, 4H), 2.54-2.76 (m, 1H), 1.53-1.83 (m, 2H), −0.22-1.30 (m, 7H).LCMS-ESI (POS.) m/z: 544.0 (M+H)+.

In a Sixth Illustrative Example the Compound of Example 270 is Preparedby the Process of the General Scheme for Route C:

Example 270: Preparation of(1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamideStep 1:(1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide

To a rt solution of(1R,3R,5R)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (Intermediate 5.0, 47 mg, 0.151 mmol),(R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methanaminehydrochloride (Intermediate 9.5, 37 mg, 0.138 mmol),hydroxybenzotriazole (37 mg, 0.275 mmol) and0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(104 mg, 0.275 mmol) in DMF (0.6 mL) was added DIPEA (0.24 mL, 1.38mmol). The resulting mixture was stirred at rt for 20 min then dilutedwith water (0.5 mL) and extracted with EtOAc (2×1 mL). The organic phasewas dried and concentrated to a viscous oil which was purified byreverse phase HPLC (10%-100% water (w/0.1% TFA)/acetontrile (w/0.1%TFA), 40 min gradient, Phenomonex Gemini 5 μm C18 column) to provide thedesired product (68.0 mg, 0.130 mmol) as a white foam. ¹H NMR (DMSO-d₆)δ: 8.74 (d, J=7.5 Hz, 1H), 8.18 (t, J=1.8 Hz, 1H), 8.09-7.99 (m, 2H),7.79 (t, J=7.8 Hz, 1H), 7.74-7.59 (m, 2H), 4.96 (dd, J=11.5, 3.5 Hz,2H), 4.58 (t, J=7.9 Hz, 2H), 3.27 (s, 3H), 1.82-1.60 (m, 3H), 1.13-1.05(m, 1H), 0.82-0.66 (m, 2H), 0.56 (d, J=8.0 Hz, 1H), 0.47 (d, J=8.4 Hz,1H), 0.35 (d, J=4.7 Hz, 2H). LCMS-APCI (POS.) m/z: 525.2 (M+H)+.

Preparation of Common Intermediate 5.0(1R,3R,5R)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid Step 1: Preparation of (1R,3R,5R)-ethyl2-azabicyclo[3.1.0]hexane-3-carboxylate hydrochloride

A 100 mL round-bottom flask was charged with (1R,3R,5R)-2-tert-butyl3-ethyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.0 g, 3.92 mmol,Synthonix, Inc.) and DCM (13.0 mL). To that solution was added HCl (4.0Min dioxane, 4.90 mL, 19.6 mmol). After 2.5 h at rt, the mixture wasconcentrated under reduced pressure and azeotroped with methanol (2×10mL) to give (1R,3R,5R)-ethyl 2-azabicyclo[3.1.0]hexane-3-carboxylatehydrochloride (0.751 g, 100%) as a foam. LCMS-ESI (POS.). m/z: 156.2(M+H)+.

Step 2: Preparation of (1R,3R,5R)-ethyl2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate

A 100 mL round-bottom flask was charged with (1R,3R,5R)-ethyl2-azabicyclo[3.1.0]hexane-3-carboxylate hydrochloride (0.75 g, 3.9 mmol)and DCM (20 mL). To that stirring solution at rt was added3-(methylsulfonyl)benzoic acid (1.2 g, 5.9 mmol), TBTU (1.9 g, 5.9 mmol)and DIPEA (3.4 mL, 19.6 mmol). After 24 h, the reaction mixture wasconcentrated under reduced pressure. The resulting oil was diluted withDCM, and purified by MPLC on silica gel, eluting with 0-50% EtOAc inheptane to provide (1R,3R,5R)-ethyl2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate(1.1 g, 83%). LCMS-ESI (POS.). m/z: 338.0 (M+H)+.

Step 3: Preparation of(1R,3R,5R)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid, Intermediate 5.0

To a 50 mL round-bottom flask was added (1R,3R,5R)-ethyl2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate(1.0 g, 3.0 mmol), lithium hydroxide (0.14 g, 14.8 mmol) and 1,4-dioxane(10 mL) and water (10 mL). The reaction mixture was stirred at rt for 1h, then diluted with water and acidified to pH=2 with 1N HCl. Themixture was extracted with 3:1 DCM/MeOH, and the combined organicextracts were washed with brine, dried over MgSO₄, filtered, andconcentrated under reduced pressure to afford(1R,3R,5R)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (0.81 g) as white solid. LCMS-ESI (POS.). m/z: 310.0 (M+H)+.

Preparation of Common Intermediate 9.5(R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl) methanaminehydrochloride Step 1: Preparation of(S,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide(Common Intermediate 9.5)

Copper(II) sulfate (31.2 g, 195 mmol) and(S)-2-methylpropane-2-sulfinamide (17.35 g, 143 mmol) were suspended in1,2-dichloroethane (260 mL). 2-fluoro-4-(trifluoromethyl)benzaldehyde(25 g, 130 mmol) was added, and the reaction was heated to 55° C. Themixture was filtered through a pad of celite and silica gel. The filtercake was washed with 1,2-dichloroethane, and the filtrate wasconcentrated under reduced pressure to give(S,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamideas a viscous yellow oil (38.3 g, 130 mmol). ¹H NMR (500 MHz,chloroform-d) δ ppm 8.14 (t, J=7.40 Hz, 1H), 7.51 (d, J=8.30 Hz, 1H),7.45 (d, J=9.86 Hz, 1H), 1.29 (s, 9H). LCMS (POS.) m/z: 296.0 (M+H)+.

Step 2: Preparation of(S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide

A 1 L three-neck round-bottom flask was charged with(S,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide(20.1 g) and DCM (295 mL). The solution was cooled −78° C. followed byaddition of cyclopropyl magnesium bromide (1 M solution in 2-MeTHF, 89mL, 89 mmol) at a rate of 90 mL/hr. The reaction was stirred for anadditional hour and then the cold bath was removed and the solutionallowed to warm to 0° C. To the solution was added saturated ammoniumchloride solution (150 mL) followed by water (100 mL). The layers wereseparated and the organic were washed once with saturated brinesolution, dried over sodium sulfate, and concentrated under reducedpressure to give a yellow oil (19 g). The crude product was carried onwithout purification. The stereochemistry was assigned based onliterature precedent (Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc.Chem. Res. 2002, 35, 984).

Step 3: Preparation of(R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methanaminehydrochloride (Common Intermediate 9.5)

(S)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamidewas dissolved in DCM (200 mL) followed by addition of HCl (4 M solutionin dioxane, 50 mL, 200 mmol). After stirring 1 h the product wasprecipitated by addition of heptane. The precipitate was collected byfiltration and the solids were washed with heptane and dried undernitrogen atmosphere overnight to give the desired product as a whitesolid (11.4 g, 42.3 mmol). ¹H NMR (400 MHz, chloroform-d) b ppm 0.46(dq, J=9.81, 5.13 Hz, 1H) 0.61-0.77 (m, 3H) 1.41-1.50 (m, 1H) 3.96 (brdd, J=9.38, 5.13 Hz, 1H) 7.37-7.47 (m, 2H) 7.87 (t, J=7.46 Hz, 1H) 9.17(br s, 3H).

Route D:

Example Route D: Example 749

N-methylprop-2-yn-1-amine (10.4 mg, 0.15 mmol) was added to a 4-mL vialand chilled to −30° C. To this was added a solution of3-(chlorosulfonyl)benzoic acid (0.050 g, 0.225 mmol) and DIPEA (0.065mL, 0.56 mmol) in DCM (0.750 mL). The reaction was allowed to slowlywarm to rt and stirred for an additional 1 h. A solution of(R)—N—((R)-1-(4-(trifluoromethyl)phenyl)ethyl) pyrrolidine-2-carboxamide(0.052 g, 0.180 mmol), DIPEA (0.065 mL, 0.375 mmol, 0.56 mmol), and TBTU(0.058 g, 0.180 mmol) was then added and the coupling was stirred at rtfor 12 h. The crude product was purified by preparative HPLC method(column: Xbridge or Xselect 19×100 mm, 10 μm, mobile phase: 0.1% NH₄OHin ACN and water) to give1-(3-(methyl(2-propyn-1-yl)sulfamoyl)benzoyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamideExample 749 (12 mg) as a colorless film. ¹H NMR (500 MHz, DMSO-d₆) δ ppm8.49-8.91 (m, 1H), 7.50-8.04 (m, 8H), 4.84-5.27 (m, 1H), 3.99-4.48 (m,2H), 3.59-3.68 (m, 1H), 3.39-3.54 (m, 3H), 2.69-3.15 (m, 4H), 2.69-3.19(m, 1H), 1.68-2.06 (m, 4H), 1.31-1.46 (m, 3H). LCMS-ESI (POS.) m/z:522.2 (M+H)+.

Route E

Example Route E: Example 790

The procedure described for Route A was performed employing3,5-dichlorobenzylamine and Intermediate 1.3 followed by the subsequentmanipulation:

Step 2: Crude tert-butyl(S)-4-((3-cyanoazetidin-1-yl)sulfonyl)-2-((R)-2-((3,5-dichlorobenzyl)carbamoyl)pyrrolidine-1-carbonyl)piperazine-1-carboxylate(200 mg, 0.318 mmol) was dissolved in DCM (3.0 mL, 0.1 M) at rt. TFA(1.5 mL) was added and the reaction was stirred for 3 h and thensaturated sodium bicarbonate was added and the organics were extractedwith ethyl acetate and washed with brine. The organics were concentratedto provide1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(3,5-dichlorobenzyl)-D-prolinamideExample 790 (32 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ8.28-8.78 (m, 1H), 8.03-8.25 (m, 1H), 7.30-7.61 (m, 1H), 7.22-7.25 (m,1H), 4.22-4.39 (m, 3H), 4.01-4.14 (m, 2H), 3.88-3.98 (m, 2H), 3.70-3.88(m, 2H), 3.30-3.62 (m, 6H), 2.91-3.06 (m, 1H), 2.68-2.78 (m, 2H),1.74-2.16 (m, 4H). LCMS-ESI (POS.) m/z: 529.0 (M+H)+.

Route F

Example Route F: Example 157

The procedure described for Route A was performed employing(4-(aminomethyl)phenyl)methanol and Intermediate 3.0 followed by thesubsequent manipulation:

Step 2:(R)-1-(3-((3-cyanoazetidin-1-yl)sulfonyl)benzoyl)-N-(4-(hydroxymethyl)benzyl)pyrrolidine-2-carboxamide(332 mg, 0.688 mmol) was dissolved in dichloromethane (3.4 mL) andcooled to −78° C. To this was added 1.0M DAST in DCM (1.0 mL, 1.03 mmol)dropwise. The reaction was stirred at −78° C. for 1 h and then allowedto warm to rt. The mixture was concentrated under reduced pressure andpurified by preparative HPLC (XSelect CSH Prep C18 10 μm ODB 19×100 mm,A: water 0.1% TFA B: acetonitrile 0.1% TFA, gradient: 25% (2 min),25-70% (12 min), flow rate: 40 mL/min, monitored @ 215 nm) to give1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(fluoromethyl)benzyl)-D-prolinamideExample 157 (8.7 mg) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm8.57 (t, J=5.97 Hz, 1H), 7.62-8.06 (m, 4H), 6.94-7.44 (m, 4H), 5.38-5.47(m, 1H), 5.29-5.35 (m, 1H), 3.78-4.55 (m, 8H), 3.60-3.67 (m, 2H),2.17-2.31 (m, 1H), 1.76-1.97 (m, 3H). LCMS-ESI (POS.) m/z: 485.2 (M+H)+.

Route G

Example Route G: Example 558

The procedure described for Route A was performed employing Intermediate11.0 and Intermediate 1.0 followed by the subsequent manipulation:

Step 2: tert-Butyl3-((R)-(4-chloro-2,5-difluorophenyl)((R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)pyrrolidine-2-carboxamido)methyl)azetidine-1-carboxylatewas dissolved in DCM (2.2 mL) at rt. TFA (0.675 mL, 8.76 mmol) was addedand the solution was stirred for 1 h. Saturated aqueous sodiumbicarbonate was added and the organics were extracted with ethylacetate, washed with brine, and purified by preparative HPLC (XSelectCSH Prep 018 10 μm ODB 19×100 mm, A: water 0.1% TFA B: acetonitrile 0.1%TFA, gradient: 25% (2 min), 25-70% (12 min), flow rate: 40 mL/min,monitored @ 215 nm) to give a diastereomeric mixture of(R)—N—((S)-azetidin-3-yl(4-chloro-2,5-difluorophenyl)methyl)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)pyrrolidine-2-carboxamideand(R)—N—((R)-azetidin-3-yl(4-chloro-2,5-difluorophenyl)methyl)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)pyrrolidine-2-carboxamide.The diastereomeric mixture was separated by preparative SFC method(Column: Chiralpak IC 2×15 cm, mobile phase: 55% methanol with 0.2% DEA,flowrate: 80 mL/min, 215 nm, inlet pressure: 100 bar) to deliver theboth epimers. The second eluting peak was assigned asN—((R)-3-azetidinyl(4-chloro-2,5-difluorophenyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamideExample 558 based on literature precedent (Ellman, J. A.; Owens, T. D.;Tang, T. P. Acc. Chem. Res. 2002, 35, 984). ¹H NMR (500 MHz, DMSO-d₆) δppm 7.32-8.67 (m, 3H), 5.06-5.38 (m, 1H), 4.21-4.51 (m, 1H), 3.97-4.11(m, 2H), 3.84-3.96 (m, 2H), 3.74-3.81 (m, 1H), 3.51-3.64 (m, 3H),3.43-3.49 (m, 1H), 3.08-3.29 (m, 3H), 2.69-3.04 (m, 3H), 2.56-2.68 (m,1H), 1.63-2.25 (m, 7H), 1.11-1.56 (m, 3H). LCMS-ESI (POS.) m/z: 585.2(M+H)+.

Route H

Example Route H: Example 310

The procedure described for Route C was performed employing Intermediate9.3,(1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid, and 3-iodobenzoic acid followed by the subsequent manipulation:

Step 4:(1R,3R,5R)—N—((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-iodobenzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(126 mg, 0.22 mmol), 1,10-phenanthroline (0.016 g, 0.089 mmol),copper(I) iodide (1.5 mg, 0.045 mmol), and cyclopropanesulfinic acidsodium salt (5.8 mg, 0.33 mmol) were added to a 8 mL reaction vial.Dimethyl sulfoxide (0.90 mL) was added, the vial was sealed with aTeflon cap and heated at 85° C. for 12 h. The mixture was then cooled tort and purified by preparative HPLC (XSelect CSH Prep C18 10 μm ODB19×100 mm, A: water 0.1% TFA B: acetonitrile 0.1% TFA, gradient: 25% (2min), 25-70% (12 min), flow rate: 40 mL/min, monitored @ 215 nm) to give(1R,3R,5R)—N—((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(cyclopropylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamideExample 310 (56 mg) as a white solid. ¹H NMR (500 MHz, chloroform-d) δppm 8.23-8.29 (m, 1H), 7.96-8.08 (m, 2H), 7.65-7.75 (m, 1H), 7.48-7.59(m, 2H), 7.14-7.25 (m, 2H), 5.13-5.22 (m, 1H), 4.26-4.39 (m, 1H),3.24-3.32 (m, 1H), 2.54-2.63 (m, 1H), 2.47-2.54 (m, 1H), 2.35-2.45 (m,1H), 1.72-1.85 (m, 1H), 1.32-1.44 (m, 2H), 1.03-1.26 (m, 4H), 0.85-0.96(m, 1H), 0.52-0.71 (m, 2H), 0.31-0.46 (m, 2H). LCMS-ESI (POS.) m/z:551.2 (M+H)+.

Route I

Example Route I: Example 481

Step 1: To a 40-mL vial was added (4-(trifluoromethyl)phenyl)methanamine(0.32 g, 1.84 mmol), (S)-(−)-indoline-2-carboxylic acid (0.30 g, 1.84mmol), ethyl acetate (6.1 mL), pyridine (3.1 mL), and1-propanephosphonic acid cyclic anhydride (1.84 mL, 1.84 mmol). The vialwas capped and heated to 50° C. for 1 h. The reaction was concentratedand purified by silica gel chromatography using 0-50% EtOAc/heptane togive (rac)-N-(4-(trifluoromethyl)benzyl)indoline-2-carboxamide (0.336g). LCMS-ESI (POS.) m/z: 321.2 (M+H)+.

Step 2: To a 20-mL vial was added3-((3-cyanoazetidin-1-yl)sulfonyl)benzoic acid (Intermediate 3.1, 0.304g, 1.143 mmol), N-(4-(trifluoromethyl)benzyl)indoline-2-carboxamide(0.366 g, 1.143 mmol), ethyl acetate (3.81 mL), pyridine (1.90 mL), and1-propanephosphonic acid cyclic anhydride (1.5 mL, 1.485 mmol). The vialwas capped and heated to 50° C. for 1 h, then cooled to rt and purifiedby preparative HPLC (Xselect 19×100 mm, 10 μm, mobile phase: 0.1% NH₄OHin ACN and water) to provide both(2R)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-indole-2-carboxamideand(2S)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-indole-2-carboxamide(Example 481) (0.021 g) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δppm 7.87-8.09 (m, 3H), 7.87 (br s, 1H), 7.77-7.84 (m, 1H), 7.71 (br d,J=7.66 Hz, 1H), 7.60-7.67 (m, 2H), 7.56 (br d, J=7.66 Hz, 1H), 7.44 (brs, 1H), 7.36 (br d, J=7.27 Hz, 1H), 7.21-7.31 (m, 2H), 7.15-7.21 (m,1H), 7.07-7.15 (m, 1H), 6.88-7.07 (m, 1H), 4.27 (br s, 1H), 4.08 (br d,J=5.06 Hz, 1H), 3.94-4.04 (m, 2H), 3.80-3.93 (m, 2H), 3.05 (s, 1H).LCMS-ESI (POS.) m/z: 569.2 (M+H)+.

Route J

Example Route J: Example 712

The procedure described for Route C was performed employing4-trifluoromethylbenzylamine and D-Boc-proline followed by thesubsequent manipulations:

Step 4: tert-Butyl(S)-3-((R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-carboxylate(4.48 g, 9.27 mmol) was dissolved in DCM (50 mL). While at rt, TFA (25mL) was added slowly, and the reaction mixture was stirred at rt for 1h. The solvent was evaporated, and the residue was dissolved in DCM andwashed with 2N NaOH. The organic layers were dried over MgSO₄, filtered,and concentrated under reduced pressure to provide crude(R)-1-((S)-piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide(3.55 g). LCMS-ESI (POS) m/z: 384.2 (M+H)+.

Step 5:(R)-1-((S)-piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide(2.74 g, 7.15 mmol) was dissolved in DCM (84.0 mL) and cooled to −30° C.To this solution was added DIPEA (2.49 mL, 14.30 mmol) and sulfurylchloride (1.74 mL, 21.45 mmol). The reaction mixture was allowed to warmto rt and stir for 1 h. The solvent was evaporated, and the mixture waspurified by MPLC using silica gel (230-400 mesh) and eluted with agradient of 5-50% 3:1 EtOAc/EtOH in heptane to provide(S)-3-((R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-sulfonylchloride (Intermediate 24, 2.88 g). ¹H NMR (500 MHz, chloroform-d) δ7.58 (d, J=8.17 Hz, 2H), 7.37 (br d, J=8.04 Hz, 3H), 4.61 (dd, J=2.21,8.04 Hz, 1H), 4.49-4.57 (m, 1H), 4.38-4.47 (m, 1H), 3.92 (br dd, J=1.88,12.00 Hz, 2H), 3.45-3.70 (m, 2H), 3.03 (t, J=11.68 Hz, 1H), 2.82-2.89(m, 1H), 2.76-2.81 (m, 1H), 2.44 (qdd, J=3.00, 6.34, 9.33 Hz, 1H),2.14-2.30 (m, 1H), 2.01-2.11 (m, 1H), 1.89-1.99 (m, 3H), 1.74-1.86 (m,1H), 1.44-1.57 (m, 1H).

Step 6: To a solution of(S)-3-((R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-sulfonylchloride (95 mg, 0.18 mmol) and 6,6-difluoro-2-azaspiro[3.3]heptanehydrochloride (100 mg, 0.59 mmol) in DMF (1.9 mL) at rt was addedtriethylamine (0.28 mL, 1.97 mmol). The reaction mixture was stirred for12 h at rt and then purified by reverse-phase HPLC (25-70% MeCN/water)to afford(R)-1-((S)-1-((3-(dimethylcarbamoyl)azetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamideExample 712 (72 mg) as a white powder. ¹H NMR (400 MHz, chloroform-d) δ7.55-7.65 (m, 2H), 7.45-7.54 (m, 1H), 7.32-7.44 (m, 2H), 4.61 (dd,J=1.97, 7.98 Hz, 1H), 4.47-4.55 (m, 1H), 4.35-4.45 (m, 1H), 4.10-4.18(m, 2H), 4.03 (dt, J=3.84, 8.24 Hz, 2H), 3.76-3.86 (m, 2H), 3.60 (dd,J=5.23, 8.76 Hz, 2H), 3.47-3.56 (m, 1H), 2.90-3.01 (m, 4H), 2.86-2.90(m, 3H), 2.67-2.84 (m, 2H), 2.42-2.52 (m, 1H), 2.11-2.25 (m, 1H),1.98-2.11 (m, 1H), 1.82-1.95 (m, 2H), 1.73-1.82 (m, 1H), 1.58-1.65 (m,1H), 1.49-1.58 (m, 1H). LCMS-ESI (POS.) m/z: 574.2 (M+H)+.

Route K

Example Route K: Example 377

The procedure described for Route A was performed employing Intermediate9.5 and Intermediate 23.0 followed by the subsequent manipulation:

Step 2: To a 10-mL vial was added(R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylthio)benzoyl)-2,3-dihydro-1H-pyrrole-2-carboxamide(0.06 g, 0.125 mmol) in DCM (1.2 mL). After cooling to 0° C., MCPBA (77wt %, 0.051 g, 0.226 mmol) was added in 3 portions. The mixture wasstirred at 0° C. for 30 min and then diluted with DCM and washed with a1N NaOH solution. The aqueous fraction was extracted with DCM, and thecombined organic layers were dried over MgSO₄, filtered, andconcentrated. The residue was purified by Gilson reverse-phase H PLC(25-70% ACN/water) to provide(2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2,3-dihydro-1H-pyrrole-2-carboxamideExample 377 (0.008 g) as white powder. ¹H NMR (500 MHz, chloroform-d) δppm 8.16 (s, 1H), 8.11 (br d, J=7.79 Hz, 1H), 7.86 (d, J=7.66 Hz, 1H),7.69-7.77 (m, 2H), 7.48-7.54 (m, 1H), 7.43 (d, J=8.04 Hz, 1H), 7.36 (d,J=10.38 Hz, 1H), 6.31-6.37 (m, 1H), 5.33-5.39 (m, 1H), 5.10 (dd, J=3.70,10.45 Hz, 1H), 4.61 (t, J=7.98 Hz, 1H), 3.21 (br dd, J=1.43, 17.26 Hz,1H), 3.10-3.14 (m, 3H), 2.76-2.98 (m, 1H), 1.26-1.35 (m, 1H), 0.61-0.69(m, 1H), 0.54-0.61 (m, 1H), 0.44-0.50 (m, 1H), 0.37-0.44 (m, 1H).LCMS-ESI (POS.) m/z: 511.0 (M+H)+.

Route L

Example Route L: Example 507

The sequence described for Route C was performed with(6-(trifluoromethyl)pyridin-3-yl)methanamine, D-Boc-proline, andIntermediate 20.0 followed by the subsequent manipulations:

Step 4: A mixture of methyl(R)-3-((3-(2-(((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)pyrrolidine-1-carbonyl)phenyl)thio)cyclobutanecarboxylate(0.15 g, 0.29 mmol) and MCPBA (77 wt %, 0.18 g, 0.81 mmol) in DCM (3 mL)was stirred at rt for 16 h. The reaction mixture was diluted with DCMand washed with 1N NaOH solution. The combined organic layers were driedover MgSO₄, filtered, and concentrated under reduced pressure. The crudematerial was then purified by MPLC using silica gel (230-400 mesh) andeluted with a gradient of 0-60% 3:1 EtOAc/EtOH in heptane, to providemethyl(R)-3-((3-(2-(((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)pyrrolidine-1-carbonyl)phenyl)sulfonyl)cyclobutanecarboxylate(0.14 g) as a light-yellow oil. LCMS-ESI (POS) m/z: 554.0 (M+H)+.

Step 5: A solution of methyl(R)-3-((3-(2-(((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)pyrrolidine-1-carbonyl)phenyl)sulfonyl)cyclobutanecarboxylate(0.16 g, 0.289 mmol) in THF (1.7M), methanol (0.6 mL), and water (0.6mL) was treated with lithium hydroxide (34.6 mg, 1.45 mmol). Thesolution was stirred at rt for 2 h, then diluted with water andacidified with 1N HCl solution to pH=3. The mixture was extracted withEtOAc/EtOH (3:1), and the combined organic layers were dried over MgSO₄,filtered, and concentrated under reduced pressure. The resulting crudeacid was used without purification. LCMS-ESI (POS) m/z: 540.1 (M+H)+.

Step 6: This crude acid from above was suspended in DCM (2 mL) andtreated with 1-chloro-N,N,2-trimethyl-1-propenylamine (0.058 mL, 0.434mmol). After 1 h, NH₃ (0.5M solution in 1,4-dioxane, 2.89 mL, 1.45 mmol)was added in one portion, and the mixture was stirred at rt for 12 h.The solvent was evaporated, and the residue was purified by MPLC usingsilica gel (230-400 mesh) and eluted with a gradient of 10-100% 3:1EtOAc/EtOH in heptane, to provide(R)-1-(3-((3-carbamoylcyclobutyl)sulfonyl)benzoyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrrolidine-2-carboxamide (0.135 g) as off-white powder. LCMS-ESI (POS)m/z: 539.2 (M+H)+.

Step 7: A solution of(R)-1-(3-((3-carbamoylcyclobutyl)sulfonyl)benzoyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrrolidine-2-carboxamide(0.135 g, 0.251 mmol) and pyridine (0.12 mL, 1.50 mmol) in DCM (2.5 mL)was cooled to 0° C. TFAA (0.087 mL, 0.627 mmol) was added dropwise andthe reaction mixture was allowed to warm to rt and stir for anadditional 2 h. The solvent was evaporated under reduced pressure andthe residue was purified by MPLC using silica gel (230-400 mesh) andeluted with a gradient of 0-50% 3:1 EtOAc/EtOH in heptane to provide(R)-1-(3-((3-cyanocyclobutyl)sulfonyl)benzoyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrrolidine-2-carboxamide(Example 507, 0.063 g) as colorless oil. ¹H NMR (500 MHz, DMSO-d₆) δ ppm8.38-8.81 (m, 2H), 7.53-8.15 (m, 6H), 4.03-4.60 (m, 5H), 3.37-3.68 (m,3H), 3.13-3.22 (m, 1H), 2.53-2.68 (m, 4H), 2.18- 2.35 (m, 1H), 1.76-2.00(m, 3H). LCMS-ESI (POS.) m/z: 521.0 (M+H)+.

Route M

Example Route M: Example 240

The sequence described for Route C was performed with4-trifluoromethylbenzylamine, Boc-cis-4-hydroxy-D-proline,(S)—N-Boc-piperidine-3-carboxylic acid followed by the subsequentmanipulations:

Step 4a: A 40 mL pressure release vial was charged with (S)-tert-butyl3-((2R,4R)-4-hydroxy-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidine-1-carboxylate(645 mg, 1.291 mmol) and dissolved in ethyl acetate (6.5 mL). To thatsolution was added HCl, 4.0M in dioxane (3.2 mL, 12.91 mmol). The vialwas sealed and placed and stirred at room temperature. After 4 hours,LCMS showed complete consumption of the starting material to polar peakcontaining a mass consistent with the desired product. The reactionmixture was concentrated under reduced pressure. The resulting whitefilm was dissolved with DCM and ethyl acetate was added until thesolution became faintly turbid. After 20 minutes, the white solids werecollected by filtration to give(2R,4R)-4-hydroxy-1-((S)-piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamidehydrochloride (390 mg, 0.895 mmol) as a white solid. LCMS-ESI (POS.)m/z: 400.2 (M+H)+.

Step 4b: A 40 mL pressure vial was charged with(2R,4R)-4-hydroxy-1-((S)-piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamidehydrochloride (200 mg, 0.459 mmol) and dissolved in DMF (2.0 mL). Tothat solution was added triethylamine (0.638 mL, 4.59 mmol) followed by3-cyanoazetidine-1-sulfonyl chloride (249 mg, 1.377 mmol). The vial wassealed and the reaction was let stir overnight. After 20 hours, LCMSshowed complete consumption of the starting material to a peakcontaining a mass consistent with the desired product (m/z=563+H). Thecrude reaction was filtered through a 0.45p syringe tip filter, andpurified by preparative HPLC: 50 μm Silica Gel 19×100 mm XSelect CSHPrep C18 10 μm ODB 19×100 mm, A: water 0.1% TFA B: acetonitrile 0.1%TFA, Gradient: 25% (2 min), 25-70% (12 min), Flow Rate: 40 mL/min, 3injections monitored @215 nm. The fractions containing product weretransferred into a recovery flask and the acetonitrile was removed untilthe solution became turbid. After which, the turbid solution waslyophilized to give(2R,4R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-4-hydroxy-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide(also referred to as(4R)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-hydroxy-N-(4-(trifluoromethyl)benzyl)-D-prolinamide)Example 240 (49.7 mg, 0.091 mmol) as a fluffy white solid. ¹H NMR (500MHz, chloroform-d) δ ppm 7.50-7.66 (m, 3H), 7.38 (br s, 2H), 4.69 (br d,J=7.66 Hz, 1H), 4.55-4.64 (m, 1H), 4.52 (br s, 1H), 4.41 (br d, J=14.53Hz, 1H), 3.99-4.17 (m, 4H), 3.60-3.81 (m, 4H), 3.42 (br s, 1H), 2.93 (brt, J=11.16 Hz, 1H), 2.76 (br t, J=11.42 Hz, 1H), 2.60 (br s, 1H),2.31-2.44 (m, 1H), 2.19 (br s, 1H), 1.23-1.98 (m, 5H). LCMS-ESI (POS.)m/z: 544.2 (M+H)+.

Route N

Example Route N: Example 653

Steps 1 and 2 of Route C were conducted with Intermediate 9.5 and(R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid followed by thesubsequent manipulation.

Step 3: Chamber A of a COware two-chamber system with stir bars wascharged with potassium fluoride (14.1 mg, 0.243 mmol) andmethyldiphenylsilanecarboxylic acid (58.8 mg, 0.243 mmol). Chamber B wasthen charged with 6-bromo-2,3-dihydrobenzo[b]thiophene-1,1-dioxide (50.0mg, 0.202 mmol),(R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)piperidine-2-carboxamidehydrochloride (154 mg, 0.405 mmol), 1,4-dioxane (270 μL),methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2methylamino-1,1 biphenyl-2-yl)palladium(II) (9.7 mg, 10.1 μmol) andtriethylamine (114 μL, 0.809 mmol). The vessel was sealed and purgedwith nitrogen gas followed by addition of dioxane (270 μL) to chamber A.The vessel was heated to 60° C. overnight with rapid stirring. Thesolution from chamber B was directly purified by silica gelchromatography using 0-50% EtOAc in heptane to give the desired productas a white solid((2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((1,1-dioxido-2,3-dihydro-1-benzothiophen-6-yl)carbonyl)-2-piperidinecarboxamideExample 653, 56.2 mg, 0.104 mmol). ¹H NMR (500 MHz, chloroform-d) δ ppm7.83 (br s, 1H), 7.70 (br d, J=7.01 Hz, 1H), 7.31-7.55 (m, 5H), 7.14 (brd, J=5.71 Hz, 1H), 5.22 (br s, 1H), 4.57 (br t, J=7.40 Hz, 1H),3.36-3.77 (m, 6H), 2.99-3.25 (m, 1H), 2.25 (br d, J=13.75 Hz, 1H),1.18-2.03 (m, 17H), 0.54-0.83 (m, 2H). LCMS-ESI (POS) m/z: 561.2(M+Na)+.

Route O

General Scheme for Route O:

Example Route O: Example 306

The sequence described for Route C was performed using Intermediate 8.0,(1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid, and Intermediate 18.0 followed by the subsequent manipulation:

Step 4: A 1-dram vial with stir bar was charged with methyl2-((3-((1R,3R,5R)-3-(((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carbonyl)phenyl)sulfonyl)acetate(75 mg, 0.125 mmol), lithium hydroxide (15.0 mg, 0.624 mmol) and THF(416 μL) and water (83 μL). The reaction was heated at 40° C. for 72hours and then concentrated and purified by reverse phase HPLC XSelectCSH Prep C18 10 μm ODB 19×100 mm, A: water 0.1% TFA B: acetonitrile 0.1%TFA, gradient: 25% (2 min), 25-70% (12 min), flow Rate: 40 mL/min,monitored @ 254 nm to afford((3-(((1R,3R,5R)-3-(((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)carbonyl)phenyl)sulfonyl)aceticacid Example 306 (34.5 mg) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δppm 13.28 (br d, J=1.30 Hz, 1H), 8.71 (d, J=7.27 Hz, 1H), 8.39 (br d,J=7.01 Hz, 1H), 8.20 (s, 1H), 7.95-8.12 (m, 2H), 7.19-7.83 (m, 4H), 4.95(dd, J=11.29, 3.50 Hz, 1H), 4.43-4.68 (m, 4H), 4.02-4.16 (m, 1H),3.72-3.77 (m, 1H), 3.22 (td, J=6.16, 2.47 Hz, 1H), 2.52-2.77 (m, 2H),1.62-1.79 (m, 2H), 1.51 (s, 1H), 1.12-1.32 (m, 1H), 1.00-1.12 (m, 1H),0.66-0.80 (m, 1H), 0.23-0.64 (m, 4H). LCMS-ESI (POS.) m/z: 587.0 (M+H)+.

Route P

Example Route P: Example 523

The sequence described for Route C was performed using Intermediate 9.5,D-Boc-proline, and Intermediate 17.1 followed by the subsequentmanipulation:

Step 4: A 2-dram vial with a stir bar was charged with the(2R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(2,2,2-trifluoro-1-hydroxyethyl)benzoyl)pyrrolidine-2-carboxamide(29.6 mg, 0.056 mmol), Dess-Martin Periodinane (23.6 mg, 0.056 mmol),and dichloromethane (222 μL). The reaction stirred at rt for 16 hoursand then concentrated and purified by reverse phase HPLC (XSelect CSHPrep C18 10 μm ODB 19×100 mm, A: water 0.1% TFA B: acetonitrile 0.1%TFA, gradient: 25% (2 min), 25-95% (12 min), flow Rate: 40 mL/min,monitored @254 nm to give(R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzoyl)pyrrolidine-2-carboxamide,also referred to asN—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzoyl)-D-prolinamide(Example 523) as a white solid (25.3 mg). ¹H NMR (500 MHz, DMSO-d₆) δppm 8.67-8.77 (m, 1H), 7.27-8.18 (m, 9H), 4.55-4.67 (m, 1H), 4.49-4.55(m, 1H), 4.10-4.41 (m, 1H), 3.35-3.69 (m, 3H), 3.28-3.30 (m, 1H),2.12-2.25 (m, 1H), 1.58-1.88 (m, 4H), 1.11-1.31 (m, 2H), 0.26-0.67 (m,4H). LCMS-ESI (POS.) m/z: 549.2 (M+H)+.

Route Q

Example Route Q: Example 752

The sequence described for Route C was performed using Intermediate 9.2,(1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid, and 3-(methylsulfinyl)benzoic acid followed by the subsequentmanipulation:

Step 4: A 1-dram vial with a stir bar was charged with(1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfinyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(107.4 mg, 0.211 mmol), ammonium carbamate (49.5 mg, 0.634 mmol),(diacetoxyiodo)benzene (102 mg, 0.317 mmol) and acetonitrile (422 μL).The reaction was stirred at rt for 72 hours and then concentrated. Thecrude mixture was purified by reverse phase HPLC XSelect CSH Prep C18 10μm ODB 19×100 mm, A: water 0.1% TFA B: acetonitrile 0.1% TFA, gradient:25% (2 min), 25-95% (12 min), flow Rate: 40 mL/min, monitored @ 254 nmto give(1R,3R,5R)—N—((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-(S-methylsulfonimidoyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamideExample 752 as a white solid (42.4 mg). ¹H NMR (500 MHz, DMSO-d₆) δ ppm8.62 (br d, J=7.53 Hz, 1H), 8.21-8.43 (m, 1H), 7.29-8.20 (m, 5H),4.61-5.02 (m, 1H), 3.96-4.57 (m, 1H), 3.04-3.88 (m, 5H), 2.52-2.79 (m,2H), 1.53-1.86 (m, 2H), 1.02-1.35 (m, 2H), −0.29-0.97 (m, 6H). LCMS-ESI(POS.) m/z: 508.0 (M+H)+.

Route R

Example Route R: Example 577

Step 1:(R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)pyrrolidine-2-carboxamide(Intermediate 28.2, 0.020 g, 0.061 mmol), 3-(3-fluorooxetan-3-yl)benzoicacid (Intermediate 35.0, 0.012 g, 0.061 mmol),bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) (0.031 g,0.067 mmol) in dry dichloromethane (1 mL) was added DIPEA (0.021 mL,0.12 mmol). The reaction mixture was stirred for 30 min, concentratedunder reduced pressure, and purified by reverse phase HPLC (Phenomenex,gemini 5 μm C18 150×21.2 mm, 10-80% acetonitrile in water with 0.1%formic acid in 25 minutes) to giveN—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(3-fluoro-3-oxetanyl)benzoyl)-D-prolinamideExample 577 as a clear colorless oil (0.022 g, 0.043 mmol). ¹H NMR (400MHz, methanol-d₄) δ 7.84-7.37 (m, 7H), 5.13-5.01 (m, 2H), 5.00-4.89 (m,2H), 4.66-4.11 (m, 2H), 3.74-3.46 (m, 2H), 2.38-2.25 (m, 1H), 2.00-1.78(m, 3H), 1.35-0.96 (m, 1H), 0.74-−0.04 (m, 4H). LCMS-APCI (POS.) m/z:509.20 (M+H)+.

Route S

Example Route S: Example 780

The sequence described for Route M was performed using4-(trifluoromethyl)phenyl)methanamine, D-Boc-proline, and(S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid followed by thesubsequent manipulation:

Step 5: To a solution of(R)-1-((S)-piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamidehydrochloride (Intermediate 27.0) (0.386 g, 0.776 mmol) in dry DCM (1.0mL) at 0° C. was added DIPEA (0.257 mL, 1.55 mmol). The sample wasstirred for 15 min at rt then cooled to 0° C. While at 0° C.cyclobutanesulfonyl chloride (248 g, 1.16 mmol) was added slowly. Themixture was stirred at 0° C. for 20 min and then quenched with methanoland concentrated under reduced pressure. The mixture was dissolved inDMF and purified by reverse phase HPLC (40 min gradient with 10-100%acetonitrile in water (0.1% formic acid modifier), Phenomonex Gemini 5μm C18 150×21.20 mm column) to give (R)-1-((S)-1-(cyclobutylsulfonyl)piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide(Example 780, 0.212 g, 0.379 mmol) as a white solid. ¹H NMR (400 MHz,methanol-d₄) δ ppm 7.64 (d, J=8.1 Hz, 2H), 7.50 (d, J=7.9 Hz, 2H), 4.48(d, J=2.2 Hz, 2H), 4.44 (dd, J=4.4, 8.3 Hz, 1H), 3.93-4.03 (m, 1H),3.70-3.77 (m, 3H), 2.73-2.83 (m, 2H), 2.43-2.53 (m, 3H), 2.24-2.37 (m,4H), 1.94- 2.12 (m, 7H), 1.50-1.65 (m, 2H). LCMS-APCI (POS.) m/z: 502.2(M+H)+.

Route T

Example Route T: Example 550

The sequence described for Route R was performed using Intermediate 28.2and 2-fluoro-5-(methylsulfonyl)benzoic acid followed by the subsequentmanipulation:

Step 2: To a solution of(R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-fluoro-5-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide(0.40 g, 0.075 mmol) and DIPEA (0.80 mL, 0.88 mmol) in DMSO (0.80 mL)was added azetidine-3-carbonitrile (92.86 mg, 1.13 mmol), and thesolution was allowed to stir at 80° C. for 6 h. It was washed with asaturated aqueous NaHCO₃ and the aqueous layer was extracted extensivelywith DCM. The combined organic layers were concentrated under reducedpressure then dissolved in DMF and purified by reverse phase HPLC (40min gradient with 10-100% acetonitrile in water (0.1% formic acidmodifier), Phenomonex Gemini 5 μm C18 150×21.20 mm column) to give(R)-1-(2-(3-cyanoazetidin-1-yl)-5-(methylsulfonyl)benzoyl)-N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)pyrrolidine-2-carboxamide (Example 550, 0.014 g, 0.024 mmol) as anamorphous solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.71-8.81 (m, 1H), 8.46(dd, J=7.3, 16.3 Hz, 1H), 8.09 (ddd, J=2.4, 4.6, 8.6 Hz, 1H), 7.87-7.97(m, 1H), 7.48-7.79 (m, 5H), 4.46-4.69 (m, 3H), 4.26-4.38 (m, 2H), 4.16(dd, J=8.9, 17.1 Hz, 2H), 3.97-4.11 (m, 1H), 3.82-3.93 (m, 1H),3.51-3.61 (m, 1H), 3.11-3.31 (m, 4H), 2.13-2.28 (m, 2H), 1.67-1.90 (m,4H), 1.22 (dd, J=4.6, 8.1 Hz, 1H), 0.96 (d, J=6.4 Hz, 2H), 0.85-0.93 (m,1H), 0.58-0.64 (m, 1H), 0.47-0.51 (m, 1H), 0.38-0.47 (m, 2H), 0.27-0.36(m, 1H), −0.02 (d, J=49.1 Hz, 2H). LCMS-APCI (POS.) m/z: 593.2 (M+H)+.

Route U

Example Route U: Example 476

The sequence described for Route C was performed using Intermediate28.10 and(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid,followed by the subsequent manipulation:

Step 3: A 8 mL vial was charged with 2-(difluoromethyl)isonicotinic acid(30 mg, 0.173 mmol), HBTU (98 mg, 0.26),(2R,4R)—N—((R)-(4-chloro-2,5-difluorophenyl)(oxetan-3-yl)methyl)-4-hydroxypyrrolidine-2-carboxamide(60 mg, 0.173 mmol) and DCM (1 mL). Triethylamine (0.241 mL, 1.73 mmol)was subsequently added dropwise. After stirring for 20 min at rt, themixture was concentrated under reduced pressure and purified by HPLC (40min gradient with 10-100% acetonitrile in water (0.1% formic acidmodifier), Phenomonex Gemini 5 μm C18 150×21.20 mm column) to providethe di-acetylated product Example 476 (14.0 mg). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.79 (d, J=3.2, 5.1 Hz, 1H), 8.75 (d, J=5.0 Hz, 1H), 8.49(d, J=8.2 Hz, 1H), 7.75-7.79 (m, 2H), 7.71 (ddd, J=1.4, 5.1, 9.1 Hz,1H), 7.61-7.66 (m, 1H), 7.27-7.35 (m, 1H), 7.15 (td, J=2.6, 6.3, 7.1 Hz,2H), 6.86-7.11 (m, 3H), 5.50-5.57 (m, 1H), 5.17 (dd, J=8.2, 9.7 Hz, 1H),4.53 (d, J=9.1 Hz, 1H), 4.26-4.41 (m, 3H), 3.87-3.96 (m, 3H), 3.82 (t,J=6.1 Hz, 1H), 3.00-3.12 (m, 1H), 2.81 (ddd, J=4.5, 9.3, 14.1 Hz, 1H),2.28 (d, J=14.4 Hz, 1H). LCMS-APCI (POS.) m/z: 657.1 (M+H)+.

Route V

Example Route V: Example 537

The sequence described for Route A was performed using Intermediate13.11 and (R)-methyl morpholine-3-carboxylate followed by the subsequentmanipulation:

Step 2: A solution of (4-(trifluoromethyl)phenyl)methanamine (Chem-ImpexInternational, Inc.) (0.888 g, 0.507 mmol) in 1,4-dioxane (0.254 mL) wascooled to 0° C. and trimethylaluminum (6.0 mL, 2M in heptanes). Themixture was stirred for thirty minutes while being allowed to warm tort. To this mixture was added methyl(R)-4-(3-((5-azaspiro[2.3]hexan-5-yl)sulfonyl)benzoyl)morpholine-3-carboxylate(0.100 g, 0.254 mmol) and the mixture was heated at 100° C. for 12 h.The mixture was cooled to 0° C. and quenched with saturated NH₄Clsolution. It was extracted with EtOAc three times, dried over MgSO₄, andconcentrated under reduced pressure. The crude material was purified byreverse-phase HPLC (40 min gradient with 10-100% acetonitrile in water(0.1% formic acid modifier), Phenomonex Gemini 5 μm C18 150×21.20 mmcolumn) to give(R)-4-(3-((5-azaspiro[2.3]hexan-5-yl)sulfonyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)morpholine-3-carboxamide(Example 537, 0.048 g, 0.089 mmol). ¹H NMR (400 MHz, methanol-d₄) δ ppm8.00 (d, J=7.9 Hz, 2H), 7.71-7.90 (m, 2H), 7.63 (d, J=8.1 Hz, 2H),7.39-7.57 (m, 2H), 5.09 (s, 1H), 4.51 (d, J=39.6 Hz, 4H), 3.88 (s, 6H),3.64 (d, J=39.5 Hz, 2H), 3.48 (s, 1H), 3.35 (m, 1H), 0.48 (s, 4H).LCMS-APCI (POS.) m/z: 538.1 (M+H)+.

Route W

Example Route W: Example 497

The sequence described for Route R was performed using Intermediate 28.5and 3-(2-cyanopropan-2-yl)benzoic acid followed by the subsequentmanipulation:

Step 2: To a solution of(1R,3R,5R)-2-(3-(2-cyanopropan-2-yl)benzoyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(0.035 g, 0.033 mmol) and potassium carbonate (0.028 g, 0.198 mmol) inDMSO (1.0 mL) was added hydrogen peroxide (0.10 mL, 30% in water). Theresulting mixture was allowed to stir at rt for 1 h. The mixture wasthen purified by reverse phase HPLC (40 min gradient with 10-100%acetonitrile in water (0.1% formic acid modifier), Phenomonex Gemini 5μm C18 150×21.20 mm column) to give(1R,3R,5R)-2-(3-(1-amino-2-methyl-1-oxopropan-2-yl)benzoyl)-N—((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 497, 0.022 g, 0.040 mmol) as a white solid. ¹H NMR (400 MHz,methanol-d₄) δ ppm 7.88 (t, J=1.8 Hz, 1H), 7.65 (dt, J=1.4, 7.5 Hz, 1H),7.56-7.59 (m, 1H), 7.51-7.56 (m, 2H), 7.44-7.50 (m, 2H), 5.65 (d, J=10.2Hz, 1H), 4.99 (dd, J=4.2, 11.4 Hz, 1H), 4.83-4.86 (m, 1H), 4.60-4.70 (m,2H), 4.40 (t, J=0.9, 12.5 Hz, 1H), 3.51-3.61 (m, 1H), 2.57-2.68 (m, 1H),1.91 (dd, J=4.2, 13.5 Hz, 1H), 1.72-1.80 (m, 1H), 1.60 (d, J=4.1 Hz,7H), 1.22 (td, J=2.6, 5.3 Hz, 1H), 0.84-0.91 (m, 1H). LCMS-APCI (POS.)m/z: 548.2 (M+H)+.

Route X:

Example for Route X: Example 422

Step 1:(1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(0.100 g, 0.29 mmol, Intermediate 28.1),3-(1-((benzyloxy)carbonyl)-3-hydroxyazetidin-3-yl)benzoic acid (0.096 g,0.29 mmol, Intermediate 36.0), and bromotripyrrolidinophosphoniumhexafluorophosphate (0.150 g, 0.32 mmol) in dry DCM (1 mL) was addedDIPEA (0.102 mL, 0.58 mmol). The reaction mixture was stirred for 1 hand then concentrated under reduced pressure. Purification by silica gelchromatography (0-100% ethyl acetate in hexanes) to delivered thealcohol as a clear colorless oil (0.140 g, 0.22 mmol). ¹H NMR (400 MHz,dichloromethane-d₂) δ 7.91-7.31 (m, 13H), 5.15 (s, 2H), 5.14-5.09 (m,1H), 4.66-4.60 (m, 1H), 4.37-4.25 (m, 4H), 3.35-3.27 (m, 1H), 2.57-2.46(m, 1H), 2.37-2.25 (m, 1H), 1.76-1.67 (m, 1H), 1.24-1.17 (m, 1H),1.02-0.95 (m, 1H), 0.85-0.77 (m, 1H), 0.61-0.47 (m, 2H), 0.45-0.32 (m,2H). LCMS-APCI (POS.) m/z: 652.15 (M+H)+.

Step 2: Benzyl3-(3-((1R,3R,5R)-3-(((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carbonyl)phenyl)-3-hydroxyazetidine-1-carboxylate(0.140 g, 0.22 mmol) and 10% palladium on carbon (0.100 g, 0.44 mmol)were combined under an atmosphere of nitrogen followed by addition ofdry methanol (5 mL). The vessel was then purged with hydrogen andstirred overnight. The reaction mixture was put under a nitrogenatmosphere, Celite was added and then the mixture was filtered throughCelite, and concentrated under reduced pressure to give the desiredproduct as a clear colorless oil (0.109 g, 0.21 mmol). ¹H NMR (400 MHz,dichloromethane-d₂) δ 7.87-7.14 (m, 8H), 5.03-4.87 (m, 1H), 4.55-4.41(m, 1H), 4.01-3.72 (m, 1H), 3.57-3.45 (m, 1H), 3.25-3.15 (m, 1H),3.09-2.67 (m, 2H), 2.42-2.10 (m, 2H), 1.57 (s, 1H), 1.14-1.01 (m, 1H),0.93-0.81 (m, 1H), 0.74-0.64 (m, 1H), 0.48-0.32 (m, 2H), 0.31-0.13 (m,2H). LCMS-APCI (POS.) m/z: 518.20 (M+H)+.

Step 3:(1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(3-hydroxyazetidin-3-yl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(0.054 g, 0.10 mmol) in dry DCM (1 mL) was added DIPEA (0.055 mL, 0.32mmol) followed by methanesulfonyl chloride (0.024 mL, 0.32 mmol). Thereaction mixture was stirred for one hour, concentrated under reducedpressure, and purified by silica gel chromatography with a gradient to0-10% methanol in DCM to give the desired product as a clear colorlessoil (0.014 g, 0.023 mmol). LCMS-APCI (POS.) m/z: 596.10 (M+H)+.

Step 4:(1R,3R,5R)—N—((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(3-hydroxy-1-(methylsulfonyl)azetidin-3-yl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(0.014 g, 0.024 mmol) in dry DCM (1 mL) at −78° C. was added(diethylamino)sulfur trifluoride (0.006 mL, 0.048 mmol) dropwise. Thereaction mixture was stirred at −78° C. for 30 min, concentrated underreduced pressure, and purified by reverse phase HPLC (40 min gradientwith 10-100% acetonitrile in water (0.1% formic acid modifier),Phenomonex Gemini 5 μm C18 150×21.20 mm column) to give the desiredproduct as a clear colorless oil (Example 422, 0.001 g, 0.002 mmol). ¹HNMR (400 MHz, methanol-d₄) δ 8.86-8.80 (m, 1H), 8.27 (s, 1H), 8.02 (s,1H), 7.86-7.81 (m, 1H), 7.77-7.71 (m, 1H), 7.70-7.58 (m, 2H), 7.55-7.51(m, 1H), 7.49-7.43 (m, 1H), 4.52-4.30 (m, 6H), 3.12-3.06 (m, 3H), 2.73-2.64 (m, 1H), 1.97-1.91 (m, 1H), 1.81-1.75 (m, 1H), 1.35-1.24 (m, 2H),1.19-1.15 (m, 1H), 0.89-0.82 (m, 1H), 0.73-0.64 (m, 1H), 0.60-0.41 (m,3H). LCMS-APCI (POS.) m/z: 598.20 (M+H)+.

Example for Route Y: Synthesis of(1R,3R,5R)—N—((S)-(4-Chloro-2,5-difluorophenyl)(3-fluorooxetan-3-yl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 812)

Synthesis of 3-Fluorooxetane-3-carbaldehyde

(3-Fluorooxetan-3-yl)methanol (1.0 g, 9.43 mmol) was dissolved indichloromethane (15 mL) and cooled to 0° C. with an ice bath. To thesolution was added Dess-Martin periodinane (5.20 g, 12.25 mmol), portionwise. The resulting mixture was stirred overnight, during which time itwas allowed to warm to room temperature. Observed by TLC, using 70%ethyl acetate/hexanes and visualized with PMA stain, was disappearanceof starting material, a new non-polar spot with Rf˜0.75, and DMPby-products. The mixture was filtered through celite and the filtratewas concentrated to ˜¾ original volume (˜5 mL of dichloromethane) wasremoved under reduced pressure using rotary evaporator with water bathtemperature 5-10° C.). The resulting mixture was carried forward withoutfurther characterization or attempts to isolate. For the purpose ofreagent equivalents added in the following step, a quantitative yieldfor this step was used.

Synthesis of(S,E)-N-((3-Fluorooxetan-3-yl)methylene)-2-methylpropane-2-sulfinamide

The reaction mixture from Step 1 was cooled to 0° C. with an ice bath.To the cool solution of 3-Fluorooxetane-3-carbaldehyde (9.91 g, 95.2mmol) in dichloromethane (10 mL) was added portionwise(S)-(−)-2-methyl-2-propanesulfinamide (11.54 g, 95.2 mmol), followed bytitanium tetraethoxide (19.74 mL, 95.2 mmol). The ice bath was removedand the resulting mixture was stirred at room temperature for 18 hours.It was carefully quenched with 250 mL saturated aqueous sodiumbicarbonate and diluted with additional dichloromethane (300 mL). Theresulting biphasic suspension was stirred at room temperature for 30minutes and then filtered through celite. The filtered solid was washedwith dichloromethane (75 mL). The organic phase (filtrate) was washedwith saturated aqueous sodium chloride, dried over sodium sulfate andconcentrated to a colorless, viscous oil. This oil was purified withsilica gel using a gradient to 20% ethyl acetate/hexanes, providing(S,E)-N-((3-fluorooxetan-3-yl)methylene)-2-methylpropane-2-sulfinamide(5.70 g, 27.5 mmol) as a colorless oil. Care was taken to not leave thedesired product under high vacuum due to potential evaporation of thedesired product. 1H NMR (DMSO-d6) δ: 8.13 (d, J=9.2 Hz, 1H), 4.95-4.77(m, 4H), 1.17 (s, 9H).

Synthesis of(S)—N—((S)-(4-Chloro-2,5-difluorophenyl)(3-fluorooxetan-3-yl)methyl)-2-methylpropane-2-sulfinamide

To an oven dried, 100 mL, round bottom flask, under a nitrogenatmosphere, was added 1-chloro-2,5-difluoro-4-iodobenzene (2.41 g, 8.77mmol) in anhydrous THF (35 mL). The resulting solution was cooled to−100° C. with an ether/liquid nitrogen bath, and then n-butyllithium(1.6M in hexanes, 5.48 mL, 8.77 mmol) was added dropwise, keeping theinternal temperature between −90 and −100° C. The resulting yellowmixture was stirred between −90 and −100° C. for 30 minutes, and then(S,E)-N-((3-fluorooxetan-3-yl)methylene)-2-methylpropane-2-sulfinamide(2.0 g, 9.65 mmol) in THF (5 mL) was added dropwise via syringe, keepingthe internal temperature between −90 and −100° C. The resulting mixturewas stirred between −90 and −100° C. for 30 minutes and then quenched atthe same temperature by dropwise addition of saturated ammonium chloride(25 mL). The mixture was diluted with water (50 mL) and ethyl acetate(50 mL). The layers were shaken and separated and the organic phase waswashed with saturated aqueous sodium chloride, dried over sodium sulfateand concentrated to a viscous nearly colorless oil which was purifiedwith silica gel using a gradient to 50% ethyl acetate/hexanes providing(S)—N—((S)-(4-chloro-2,5-difluorophenyl)(3-fluorooxetan-3-yl)methyl)-2-methylpropane-2-sulfinamide(1.64 g, 4.6 mmol) the desired single diastereomer, as a white foam. 1HNMR (400 MHz, Methanol-d4) δ 7.58-7.37 (m, 2H), 5.28 (d, J=26.1 Hz, 1H),4.99-4.89 (m, 1H), 4.85-4.76 (m, 1H), 4.69-4.50 (m, 2H), 1.21 (s, 9H).LCMS-ESI (POS.) m/z: 356.10 (M+H)+.

Synthesis of(S)-(4-Chloro-2,5-difluorophenyl)(3-fluorooxetan-3-yl)methanamine

(S)—N—((S)-(4-Chloro-2,5-difluorophenyl)(3-fluorooxetan-3-yl)methyl)-2-methylpropane-2-sulfinamide(1.63 g, 4.57 mmol) was dissolved in methanol (15 mL) and cooled to 0°C. with an ice bath. Hydrogen chloride (4M in 1,4-dioxane, 1.5 mL, 5.94mmol) was added dropwise using a syringe, and the resulting mixture wasstirred at 0° C. for 5 minutes. After which time, the ice bath wasremoved. The reaction was stirred at room temperature for 45 minutes andthe reaction progress was monitored with LC/MS. The reaction wasquenched with trimethylamine (6.33 mL, 45.7 mmol) and the resultingmixture was concentrated in vacuo, providing a white solid. This solidwas partitioned between saturated aqueous sodium bicarbonate (100 mL)and dichloromethane (100 mL). The layers were separated and the aqueousphase was extracted with additional dichloromethane (50 mL). The organicextracts were combined, dried over sodium sulfate and concentrated underreduced pressure, providing the desired product,(S)-(4-chloro-2,5-difluorophenyl)(3-fluorooxetan-3-yl)methanamine (1.08g, 3.65 mmol) as a viscous, nearly colorless oil which solidified to awhite solid while drying under high vacuum overnight. Purity wasestimated to be 85%, and the product was used in the following stepwithout additional purification. 1H NMR (Methanol-d4) δ: 7.51 (ddd,J=9.8, 6.3, 1.4 Hz, 1H), 7.38 (dd, J=9.3, 6.2 Hz, 1H), 4.87-4.75 (m,1H), 4.76-4.66 (m, 2H), 4.65-4.53 (m, 2H).

Synthesis of(1R,3R,5R)—N—((S)-(4-Chloro-2,5-difluorophenyl)(3-fluorooxetan-3-yl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 812)

To a room temperature solution of(1R,3R,5R)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (92 mg, 0.30 mmol),(S)-(4-chloro-2,5-difluorophenyl)(3-fluorooxetan-3-yl)methanamine (78mg, 0.25 mmol), hydroxybenzotriazole (50 mg, 0.37 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(141 mg, 0.37 mmol) in N-methyl-2-pyrrolidone (3.0 mL) was addedN,N-diisopropylethylamine (0.13 mL, 0.74 mmol). The resulting mixturewas stirred at room temperature for 20 minutes. It was diluted withethyl acetate (40 mL) and washed once with saturated aqueous sodiumbicarbonate (40 mL). The organic phase was dried over sodium sulfate andconcentrated to an oil which was purified with reverse phase HPLC using10-100% acetonitrile/water over 40 minutes, with formic acid present(phenomenex gemini C18 5 micron column), providing(1R,3R,5R)—N—((S)-(4-chloro-2,5-difluorophenyl)(3-fluorooxetan-3-yl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(105 mg, 0.19 mmol) as a white amorphous solid. 1H NMR (Methanol-d4) δ:8.39 (s, 1H), 8.16-8.10 (m, 2H), 7.79 (t, J=7.8 Hz, 1H), 7.46 (dd,J=9.3, 6.1 Hz, 1H), 7.39 (dd, J=9.7, 6.3 Hz, 1H), 5.98 (d, J=28.0 Hz,1H), 5.05 (dd, J=11.4, 4.3 Hz, 1H), 4.82-4.74 (m, 2H), 4.65-4.55 (m,2H), 3.33 (s, 1H), 3.19 (s, 3H), 2.77-2.63 (m, 1H), 1.95-1.86 (m, 1H),1.86-1.77 (m, 1H), 1.34-1.27 (m, 1H), 0.97-0.88 (m, 1H) LCMS-ESI (POS.)m/z: 543.10 (M+H)+.

Example for Route Z: Preparation of(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-(hydroxymethyl)-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 814)

Synthesis of 6-(methylsulfonyl)isobenzofuran-1(3H)-one

3-oxo-1,3-dihydroisobenzofuran-5-sulfonyl chloride (3.5 g, 15.05 mmol),sodium bicarbonate (2.53 g, 30.1 mmol) and sodium sulfite (3.79 g, 30.1mmol) were added to a flask with a stir bar. The flask was placed in a50 C hot bath and water (35 mL) was added. The reaction mixture wasconcentrated after two hours at 50 C. The concentrated reaction mixturewas allowed to dry on the high-vac overnight. The material was thenredissolved in DMF (35 mL); the sides of the flask were scraped with aspatula to ensure all solids were suspended in solution. Methyl iodide(4.7 mL, 75 mmol) was then added to the reaction mixture. The reactionwas allowed to stir at room temperature for three hours, at which pointit was taken up in ethyl acetate (30 mL) and washed with sodiumbicarbonate (30 mL). The mixture was separated and the aqueous layerwashed once more with ethyl acetate (30 mL). The organics were driedover magnesium sulfate, filtered, and the filtrate concentrated. Theresulting material was triturated with DCM to afford the pure product asa white solid (2.25 g). ¹H NMR (DMSO-d₆) δ: 8.39-8.26 (m, 2H), 7.98 (dd,J=8.0, 0.9 Hz, 1H), 5.56 (s, 2H), 3.34 (s, 3H).

Synthesis of 2-(hydroxymethyl)-5-(methylsulfonyl)benzoic Acid

6-(methylsulfonyl)isobenzofuran-1(3H)-one (2.25 g, 10.6 mmol) wasdissolved in methanol (9 mL) and aqueous sodium hydroxide (0.952 mg ofKOH in 27 mL H₂O) was added. The solution was refluxed at 100 C. Afterthree hours of refluxing, the reaction mixture was cooled to roomtemperature and concentrated in-vacuo. The oil was then redissolved inethyl acetate and water was added. The solution was adjusted to pH 2with 3N HCl. At this time, the layers were separated and the aqueouslayer washed with ethyl acetate a total of three times. The combinedorganics were dried over magnesium sulfate, filtered, and concentratedto give (2.441 g) of pure fine white powder that was the desiredproduct. LCMS-ESI (NEG.) m/z: 229.10 (M−H).

Synthesis of2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(methylsulfonyl)benzoic acid.To a solution of TBSCl (1.505 mL, 8.69 mmol) in toluene (5 mL) anddichloromethane (5 mL) in a 40 mL vial were added imidazole (296 mg,4.34 mmol) followed by 2-(hydroxymethyl)-5-(methylsulfonyl)benzoic acid(500 mg, 2.172 mmol). The vial was sealed and stirred at 37 C overnight.In the morning, the solution was now a suspension of white solid inclear liquid. The LCMS shows that the reaction had gone about ⅔ tocompletion. The material was worked up with dichloromethane and 1N HCl.The combined organics were dried over magnesium sulfate, filtered, andthe filtrate concentrated. The material was loaded onto a 40 g silicacolumn and purified with a gradient to 85% EA in hexanes to provide theproduct (0.47 g) as a white solid set-up. R_(f)=0.15 (SiO₂, 75%EtOAc/hexanes). LCMS-ESI (NEG.) m/z: 343.10 (M−H).

Synthesis of(1R,3R,5R)-2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(methylsulfonyl)benzoyl)-N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide

2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(methylsulfonyl)benzoic acid(35 mg, 0.102 mmol) was dissolved in DMF (0.2 mL) and DIEA (0.035 mL,0.203 mmol) and HBTU (43 mg, 0.112 mmol) was added. After one minute ofstirring,(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(40.3 mg, 0.112 mmol) was added to the reaction mixture. After fiveminutes of stirring at room temperature, the desired product wasobserved by LCMS. The reaction mixture was filtered through a 0.45 usilica plug and purified by reverse phase HPLC using 10-100%acetonitrile/water over 40 minutes (phenomenex gemini c-18 5-microncolumn), providing the product (70 mg). LCMS-ESI (pos.) m/z: 687.3(M+H)+.

Synthesis of(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-(hydroxymethyl)-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide,Example 814

(1R,3R,5R)-2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(methylsulfonyl)benzoyl)-N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(70 mg, 0.102 mmol) was dissolved in THF (0.5 mL) and TBAF (355 mg, 1.02mmol) was added. The reaction mixture was stirred at room temperaturefor one hour. The reaction mixture was then taken up in aqueous sat.ammonium chloride and extracted with dichloromethane twice. The combinedorganics were concentrated and the resulting oil redissolved in DMF,filtered through a 0.45 u silica plug and purified by reverse phase HPLCusing 10-100% acetonitrile/water over 40 minutes (phenomenex gemini c-185-micron column), providing the product (23 mg). LCMS-ESI (pos.) m/z:571.2 (M−H)⁺. ¹H NMR (DMSO-d₆) δ: 8.76 (d, J=7.4 Hz, 1H), 8.00 (dd,J=8.1, 2.0 Hz, 1H), 7.88 (d, J=1.9 Hz, 1H), 7.86-7.74 (m, 2H), 7.59 (dd,J=11.1, 5.5 Hz, 1H), 5.64 (t, J=5.7 Hz, 1H), 4.89 (dd, J=11.4, 3.2 Hz,1H), 4.71 (qd, J=15.1, 5.8 Hz, 2H), 4.54 (t, J=8.0 Hz, 1H), 3.25 (s,3H), 3.00 (td, J=6.2, 2.5 Hz, 1H), 1.80 (dd, J=13.5, 3.3 Hz, 1H),1.67-1.54 (m, 1H), 1.21 (dq, J=8.2, 4.1, 3.5 Hz, 1H), 0.97 (td, J=5.2,2.7 Hz, 1H), 0.59 (t, J=8.5 Hz, 2H), 0.55-0.45 (m, 1H), 0.40 (d, J=4.8Hz, 2H).

Example for Route AA: Synthesis of(1R,3R,5R)—N—((R)-(2,5-Difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(5-methylthiophene-2-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 816)

To a room temperature solution of(1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(34 mg, 0.09 mmol), 5-methylthiophene-2-carboxylic acid (19 mg, 0.136mmol), hydroxybenzotriazole (37 mg, 0.27 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(103 mg, 0.27 mmol) in N-methyl-2-pyrrolidone (1.0 mL) was addedN,N-diisopropylethylamine (0.8 mL, 0.45 mmol). The resulting mixture wasstirred at room temperature for 20 minutes. It was diluted with ethylacetate (15 mL) and washed once with saturated aqueous sodiumbicarbonate (15 mL). The organic phase was dried over sodium sulfate andconcentrated to an oil which was purified with reverse phase HPLC using10-100% acetonitrile/water over 40 minutes, without formic acid present(phenomenex gemini C18 5 micron column), providing(1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(5-methylthiophene-2-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(27 mg, 0.054 mmol) as an amorphous foam. 1H NMR (Methanol-d4) δ: 7.72(d, J=3.8 Hz, 1H), 7.54 (dd, J=9.5, 5.7 Hz, 1H), 7.36 (dd, J=10.6, 5.5Hz, 1H), 6.91-6.84 (m, 1H), 5.57 (d, J=10.3 Hz, 1H), 4.96 (dd, J=11.2,4.6 Hz, 1H), 4.85 (t, J=7.0 Hz, 1H), 4.70-4.59 (m, 2H), 4.39 (t, J=6.2Hz, 1H), 3.80-3.69 (m, 1H), 3.58-3.42 (m, 1H), 2.73-2.57 (m, 1H), 2.54(s, 3H), 1.93-1.74 (m, 2H), 1.26-1.16 (m, 1H), 1.05-0.93 (m, 1H).LCMS-ESI (POS.) m/z: 501.10 (M+H)+.

The compounds set forth in the following table were synthesizedfollowing the procedure described for Example 816 using known startingmaterial replacements as described.

TABLE 13 A-B Intermediate C-Ring Structure, Name and Data 28.75-methylthiophene- 2-carboxylic acid

Example 816 (1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(5-methylthiophene-2-carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamideLCMS-ESI (POS.) m/z: 501.1 (M + H)+ 28.1 2-amino-5- (methylsulfonyl)-benzoic acid

Example 813 (1R,3R,5R)-2-(2-amino-5-(methylsulfonyl)benzoyl)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 540.2 (M +H)+ 28.7 1,4-dimethyl- 1H-pyrazole- 5-carboxylic acid

Example 815 (1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(2-methoxyisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS-APCI(POS.) m/z: 512.2 (M + H)+ 28.7 1,4-dimethyl- 1H-pyrazole-5- carboxylicacid

Example 818 (1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(1,4-dimethyl-1H-pyrazole-5-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 499.2 (M +H)+ 28.7 5-methyl-1H- indazole-7- carboxylic acid

Example 820 (1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(5-methyl-1H-indazole-7-carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamideLCMS-APCI (POS.) m/z: 535.2 (M + H)+ 28.X 5-chloro-1H- indazole-7-carboxylic acid

Example 821 (1R,3R,5R)-2-(5-chloro-1H-indazole-7-carbonyl)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 539.2 (M +H)+ 28.7 5- (trifluoromethyl)- isoxazole-3- carboxylic acid

Example 823 (1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(5-(trifluoromethyl)isoxazole-3-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 540.2 (M +H)+ 28.7 3,4-dimethyl- isoxazole-5- carboxylic acid

Example 824 (1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3,4-dimethylisoxazole-5-carbonyl)-2-azabicyclo[3.1.0]hexane- 3-carboxamideLCMS-APCI (POS.) m/z: 500.2 (M + H)+ 28.7 3,5-dimethyl- isoxazole-4-carboxylic acid

(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3,5-dimethylisoxazole-4-carbonyl)-2-azabicyclo[3.1.0]hexane- 3-carboxamideLCMS-APCI (POS.) m/z: 500.2 (M + H)+ 28.7 3-(trifluoro-methyl)isoxazole- 5-carboxylic acid

(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-Amethyl)-2-(3-(trifluoromethyl)isoxazole-5-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 540.1 (M +H)+

Example of Route AB: Preparation of(1R,3R,5R)—N—((S)-1-(4-chloro-2,5-difluorophenyl)-2,2-difluoroethyl)-2-(5-(methylsulfonyl)nicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 817)

Synthesis of(R)—N—((S)-1-(4-chloro-2,5-difluorophenyl)-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide

KO^(t)Bu (8 mL, 8 mmol, 1 M in THF) was added to a solution of(R,E)-N-(4-chloro-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide(0.7 g, 2.5 mmol) and difluoromethyl trimethylsilane (0.96 g, 7.5 mmol)in 14 mL in THF at −78 C. The mixture was stirred for 5 minutes at −78 Cand monitored by LCMS. Product peak observed. The reaction wassubsequently quenched at this temperature with satd aq ammoniumchloride. The solution was partitioned between saturated aq. ammoniumchloride (20 mL) and EtOAc (20 mL). The layers were separated and theaqueous phase was extracted with additional EtOAc (20 mL). The organiclayers were combined, dried over sodium sulfate, filtered andconcentrated under vacuum, providing the desired crude as a viscous oil.The crude was purified by silica gel column chromatography (0% to 40%EtOAc/hexanes) to provide the product as a yellow viscous oil (5:1 ratioof diastereomers) (126 mg). LCMS-ESI (pos.) m/z: 332.1 (M+H)+.

Preparation of(S)-1-(4-chloro-2,5-difluorophenyl)-2,2-difluoroethan-1-amine

To a solution of(R)—N—((S)-1-(4-chloro-2,5-difluorophenyl)-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide(0.112 g, 0.34 mmol) in methanol (2 mL) at 0° C. in an ice bath underargon was added 4M HCl in dioxane (0.2 mL, 0.81 mmol) dropwise andstirred for 5 minutes. Then the reaction mixture was stirred at 0 C for30 mins and monitored by LCMS and TLC analysis. The reaction was deemedto be complete after 30 minutes. After the reaction was completed, thereaction was quenched by adding triethylamine (0.5 mL). The resultingmixture was concentrated under reduced pressure, and the remaining whitesolid was partitioned between saturated sodium bicarbonate (5 mL) andDCM (5 mL). The layers were separated and the aqueous phase wasextracted with additional DCM (5 mL). The organic layers were combined,dried over sodium sulfate, filtered and concentrated under vacuum,providing the desired product as a viscous oil (5:1 ratio ofdiastereomers) (55 mg). LCMS-ESI (pos.) m/z: 228.0 (M+H)+.

Synthesis of(1R,3R,5R)—N—((S)-1-(4-chloro-2,5-difluorophenyl)-2,2-difluoroethyl)-2-(5-(methylsulfonyl)nicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide,Example 817

A 8 mL vial was charged with(1R,3R,5R)-2-(5-(methylsulfonyl)nicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (61 mg, 0.2 mmol), HBTU (0.112 g, 0.3 mmol),(S)-1-(4-chloro-2,5-difluorophenyl)-2,2-difluoroethan-1-amine (45 mg,0.2 mmol, 5:1 ratio of diastereomer) and dissolved in DMF (1 ml).Triethyamine (0.276 mL, 1.98 mmol) was subsequently added DROPWISE andstirred for 20 mins and analyzed by LCMS. The reaction was filtered andpurified by reverse phase HPLC using 10-100% acetonitrile/water over 40minutes (phenomenex gemini c-18 5-micron column), providing the desireddiasteromers.

Major diastereomer, Intermediate 39:(1R,3R,5R)—N—((S)-1-(4-chloro-2,5-difluorophenyl)-2,2-difluoroethyl)-2-(5-(methylsulfonyl)nicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide.LCMS-ESI (pos.) m/z: 520.1 (M+H)+. ¹H NMR (DMSO-d₆) δ: 9.22 (d, J=2.3Hz, 1H), 9.20-9.14 (m, 2H), 8.51 (d, J=2.1 Hz, 1H), 7.78 (dd, J=9.3, 6.2Hz, 1H), 7.59 (dd, J=9.7, 6.2 Hz, 1H), 6.31 (td, J=54.9, 3.6 Hz, 1H),5.63-5.41 (m, 1H), 5.04 (dd, J=11.4, 3.6 Hz, 1H), 3.41 (s, 4H),2.72-2.58 (m, 1H), 1.84-1.69 (m, 2H), 1.11 (td, J=5.2, 2.6 Hz, 1H), 0.80(ddd, J=11.4, 7.8, 4.7 Hz, 1H).

Minor diastereomer:(1R,3R,5R)—N—((R)-1-(4-chloro-2,5-difluorophenyl)-2,2-difluoroethyl)-2-(5-(methylsulfonyl)nicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide.LCMS-ESI (pos.) m/z: 520.1 (M+H)+. ¹H NMR (Methanol-d₄) δ: 9.20 (t,J=2.1 Hz, 2H), 8.68 (t, J=2.1 Hz, 1H), 7.48 (dd, J=9.5, 6.3 Hz, 1H),7.41 (dd, J=9.3, 6.1 Hz, 1H), 6.19 (td, J=55.0, 3.0 Hz, 1H), 5.63 (ddd,J=15.6, 13.0, 3.1 Hz, 1H), 5.16 (dd, J=11.4, 4.1 Hz, 1H), 3.41 (td,J=6.2, 2.6 Hz, 1H), 3.26 (s, 3H), 2.90-2.72 (m, 1H), 2.13 (dd, J=13.6,4.0 Hz, 1H), 1.99-1.84 (m, 1H), 1.40-1.29 (m, 1H), 0.98 (dtd, J=9.1,5.6, 1.1 Hz, 1H).

Example of Route AC: Synthesis of(1R,3R,5R)—N—((R)-(2,5-Difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3-(2-hydroxypropan-2-yl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 819)

Synthesis of Methyl3-((1R,3R,5R)-3-(((R)-(2,5-Difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carbonyl)benzoate

To a room temperature solution of(1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(79 mg, 0.21 mmol), 3-(methoxycarbonyl)benzoic acid (42 mg, 0.23 mmol),hydroxybenzotriazole (57 mg, 0.42 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(159 mg, 0.42 mmol) in N-methyl-2-pyrrolidone (1.0 mL) was addedN,N-diisopropylethylamine (0.18 mL, 1.05 mmol). The resulting mixturewas stirred at room temperature for 20 minutes. It was diluted withethyl acetate (15 mL) and washed once with saturated aqueous sodiumbicarbonate (15 mL). The organic phase was dried over sodium sulfate andconcentrated to an oil which was purified with silica gel using 0-60%ethyl acetate/hexanes, providing methyl3-((1R,3R,5R)-3-(((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carbonyl)benzoate(80 mg, 0.15 mmol) as an amorphous foam. 1H NMR (Methanol-d4) δ: 8.44(t, J=1.8, 0.6 Hz, 1H), 8.21-8.14 (m, 1H), 8.07-7.97 (m, 1H), 7.63 (t,J=7.7, 0.6 Hz, 1H), 7.56 (dd, J=9.5, 5.7 Hz, 1H), 7.38 (dd, J=10.6, 5.5Hz, 1H), 5.63 (d, J=10.2 Hz, 1H), 5.00 (dd, J=11.4, 4.2 Hz, 1H),4.87-4.83 (m, 1H), 4.68 (t, J=7.8, 6.5 Hz, 1H), 4.62 (t, J=6.2 Hz, 1H),4.43-4.38 (m, 1H), 3.96 (s, 3H), 3.64-3.46 (m, 1H), 3.32-3.28 (m, 1H),2.75-2.58 (m, 1H), 1.91 (dd, J=13.6, 4.2 Hz, 1H), 1.86-1.73 (m, 1H),1.29-1.19 (m, 1H), 0.94-0.82 (m, 1H). LCMS-ESI (POS.) m/z: 539.20(M+H)+.

Synthesis of(1R,3R,5R)—N—((R)-(2,5-Difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3-(2-hydroxypropan-2-yl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 819)

Methyl3-((1R,3R,5R)-3-(((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carbonyl)benzoate(74 mg, 0.137 mmol) was dissolved in THF (5 mL) and methylmagnesiumbromide (3.0M in THF, 0.23 mL, 0.69 mmol) was added in one portion atroom temperature. The resulting mixture was stirred at room temperaturefor 15 minutes and quenched with 1 mL saturated ammonium chloride. Themixture was diluted with 15 mL water and 35 mL ethyl acetate. The layerswere shaken and separated and the organic phase was washed with brine,dried over sodium sulfate and concentrated to a crude residue which waspurified with reverse phase HPLC using 10-100% acetonitrile/water over40 minutes with no formic acid present (phenomenex gemini c-18 5-microncolumn), providing(1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3-(2-hydroxypropan-2-yl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(9 mg, 0.017 mmol) as a white solid. 1H NMR (Methanol-d4) δ: 7.94 (s,1H), 7.70-7.59 (m, 2H), 7.56 (dd, J=9.6, 5.7 Hz, 1H), 7.45 (t, J=7.8,0.5 Hz, 1H), 7.38 (dd, J=10.5, 5.5 Hz, 1H), 5.62 (d, J=10.2 Hz, 1H),4.99 (dd, J=11.4, 4.2 Hz, 1H), 4.85 (t, J=7.7, 6.6 Hz, 1H), 4.68 (t,J=7.8, 6.5 Hz, 1H), 4.62 (t, J=6.2 Hz, 1H), 4.45-4.35 (m, 1H), 3.62-3.44(m, 1H), 2.71-2.58 (m, 1H), 1.92 (dd, J=13.5, 4.1 Hz, 1H), 1.83-1.71 (m,1H), 1.58 (d, J=2.0 Hz, 7H), 1.28-1.16 (m, 1H), 0.93-0.80 (m, 1H).LCMS-ESI (POS.) m/z: 539.20 (M+H)+.

Example of Route AD:(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(5-(1-hydroxyethyl)-2-methylisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 822)

Synthesis of Benzyl(1R,3R,5R)-2-(5-bromo-2-methylisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate

A 40 mL vial was charged with 5-bromo-2-methylisonicotinic acid (1.96 g,9.06 mmol), HBTU (5.15 g, 13.58 mmol), benzyl(1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate2,2,2-trifluoroacetate (3.0 g, 9.06 mmol) and dissolved in DMF (15 ml).Triethyamine (12.6 mL, 90.6 mmol) was subsequently added DROPWISE andstirred for 20 mins and analyzed by. The reaction was deemed to becomplete. The reaction was subsequently quenched with satd aq ammoniumchloride. The layers were separated and the organic layer was washedwith satd aq sodium bicarbonate solution and brine. The organic layerswere combined, dried over sodium sulfate, filtered and concentratedunder vacuum, providing the desired crude as a viscous oil. The crudewas purified by silica gel column chromatography (0% to 40%EtOAc/hexanes) to provide the product as a yellow viscous oil (3.76 g).R_(f)=0.38 (SiO₂, 50% EtOAc/hexanes). ESI (pos.) m/z: 416.2 (M+H)+. ¹HNMR (DMSO-d₆) δ: 8.63 (s, 1H), 7.41-7.27 (m, 5H), 7.12 (s, 1H), 5.10 (d,J=1.7 Hz, 2H), 4.86 (dd, J=11.7, 3.3 Hz, 1H), 2.98 (td, J=6.1, 2.5 Hz,1H), 2.74-2.59 (m, 1H), 2.40 (s, 3H), 2.03-1.88 (m, 1H), 1.63 (dq,J=8.8, 5.8 Hz, 1H), 0.80 (td, J=5.4, 2.5 Hz, 1H), 0.68-0.47 (m, 1H).

Synthesis of Benzyl(1R,3R,5R)-2-(5-(1-ethoxyvinyl)-2-methylisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of benzyl(1R,3R,5R)-2-(5-bromo-2-methylisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate(0.3 g, 0.722 mmol) in dioxane (3.5 ml) was addedtributyl(1-ethoxylvinyl) tin (0.287 g, 0.795 mmol) anddichlorobis(triphenylphosphine)palladium(II) (5 mg, 0.007 mmol). Themixture was stirred at 100° C. for 12 h, diluted with EtOAc (15 ml), andfiltered through a thin pad of celite. The filtrate was concentratedunder reduced pressure and purified by silica gel column chromatography(SiO2, 10% to 40% EtOAc/hexanes) to provide the product as a oil. (87mg). R_(f)=0.38 (SiO₂, 50% EtOAc/hexanes). ESI (pos.) m/z: 407.2 (M+H)+.¹H NMR (Chloroform-d) δ: 8.62 (s, 1H), 7.37-7.26 (m, 5H), 7.11 (s, 1H),5.20-5.05 (m, 2H), 5.00-4.88 (m, 1H), 4.52 (d, J=3.2 Hz, 1H), 4.28 (d,J=3.1 Hz, 1H), 3.80 (q, J=7.0 Hz, 2H), 3.02 (td, J=6.3, 2.5 Hz, 1H),2.56 (s, 3H), 2.09 (dd, J=13.8, 3.4 Hz, 1H), 1.60 (dq, J=9.0, 6.0 Hz,1H), 1.23 (t, J=7.0 Hz, 3H), 0.93-0.84 (m, 1H), 0.59 (dtd, J=9.1, 6.1,1.2 Hz, 1H).

Synthesis of benzyl(1R,3R,5R)-2-(5-acetyl-2-methylisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of benzyl(1R,3R,5R)-2-(5-(1-ethoxyvinyl)-2-methylisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate(1.48 g, 3.64 mmol) in THF (25 mL) was added HCl (4 M in dioxan, 0.98mL, 39.2 mmol). The reaction was stirred overnight and monitored by LCMSanalysis. After the completion of the reaction, the solvent wasevaporated and the crude was partitioned between EtOAc and water. The aqlayer was extracted once with EtOAc and the combined organic layer wasdried, filtered, and concentrated. The crude was taken through the nextstep without further purification. (1.28 g). ESI (pos.) m/z: 379.1(M+H)+. ¹H NMR (DMSO-d₆) δ: 9.00 (s, 1H), 7.39-7.29 (m, 5H), 7.06 (s,1H), 5.11 (s, 2H), 4.85 (dd, J=11.6, 3.6 Hz, 1H), 2.90 (td, J=6.2, 2.5Hz, 1H), 2.75-2.60 (m, 1H), 2.54 (s, 3H), 2.49 (s, 3H), 2.01-1.93 (m,1H), 1.73-1.42 (m, 1H), 0.72 (td, J=5.3, 2.5 Hz, 1H), 0.62-0.48 (m, 1H).

Synthesis of benzyl(1R,3R,5R)-2-(5-(1-hydroxyethyl)-2-methylisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of benzyl(1R,3R,5R)-2-(5-acetyl-2-methylisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate(0.35 g, 0.93 mmol) in MeOH (5.0 mL) was added SODIUM BOROHYDRIDE (70mg, 1.85 mmol) in small portions. The reaction was stirred for 30 minsand monitored by LCMS analysis. After the completion of reaction, thesolvent was evaporated and the crude was partitioned between EtOAc andwater. The aq layer was extracted once with EtOAc and the combinedorganic layer was dried, filtered, and concentrated. The crude was takenthrough the next step without further purification (0.35 g; 2:1 ratio ofdiastereomers). R_(f)=0.36 (SiO₂, 100% EtOAc/hexanes). ESI (pos.) m/z:381.2 (M+H)+.

Synthesis of(1R,3R,5R)-2-(5-(1-hydroxyethyl)-2-methylisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicAcid

To a solution of benzyl(1R,3R,5R)-2-(5-(1-hydroxyethyl)-2-methylisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylate(400 mg, 1.05 mmol) in EtOAc-THF (2.5 ml, 1:1) was added palladium (20mg). The solution was purged with hydrogen for 5 mins and the mixturewas stirred at rt for 12 hr while monitoring with LCMS analysis. After12 hours LCMS analysis showed the product mass. The reaction wasfiltered over a pad of celite, concentrated, and dried. The crude wastaken through the next step without further purification (215 mg; 2:1ratio of diastereomers). ESI (pos.) m/z: 291.2 (M+H)+.

Synthesis of(1R,3R,5R)—N—((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(5-(1-hydroxyethyl)-2-methylisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide,Example 822

A 8 mL vial was charged with(1R,3R,5R)-2-(5-(1-hydroxyethyl)-2-methylisonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (113 mg, 0.39 mmol), HBTU (221 mg, 0.584 mmol),(R)-chloro(cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-15-azane(112 mg, 0.39 mmol) and dissolved in DMF (1 ml). Triethyamine (0.39 g,3.9 mmol) was subsequently added dropwise and stirred for 20 mins andanalyzed by LCMS (ac-0802-001). the reaction was deemed to be complete.The reaction was filtered and purified by reverse phase HPLC using10-100% acetonitrile/water over 40 minutes (phenomenex gemini c-185-micron column), providing the desired product (major diastereomer, 17mg). ESI (pos.) m/z: 524.2 (M+H)+. ¹H NMR (Methanol-d₄) δ: 8.61 (s, 1H),7.55-7.41 (m, 2H), 7.31 (s, 1H), 5.24-5.12 (m, 1H), 4.94 (ddd, J=11.3,3.2, 1.5 Hz, 1H), 4.50 (d, J=9.1 Hz, 1H), 3.09 (td, J=6.3, 2.7 Hz, 1H),2.72-2.61 (m, 1H), 2.55 (s, 3H), 2.01 (dd, J=13.5, 3.4 Hz, 1H),1.76-1.64 (m, 1H), 1.49 (d, J=6.6 Hz, 3H), 1.26 (tdd, J=9.5, 6.4, 4.0Hz, 1H), 1.03 (td, J=5.4, 2.5 Hz, 1H), 0.75-0.63 (m, 2H), 0.63-0.54 (m,1H), 0.54-0.41 (m, 2H).

Example of Route AE: Synthesis of(R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)((1s,3S)-3-hydroxycyclobutyl)methyl)-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide (Example 827)

A 8 mL vial was charged with acid (53 mg, 0.18 mmol), HBTU (101 mg, 0.27mmol), amine (50 mg, 0.18 mmol) and dissolved in dichloromethane (1 ml).Triethyamine was subsequently added DROPWISE and stirred for 20 mins andanalyzed by LCMS (ac-0821-001). The reaction was concentrated undervacuo, and purified by reverse phase HPLC using 10-100%acetonitrile/water over 40 minutes (phenomenex gemini c-18 5-microncolumn), providing the desired product (30 mg). ESI (pos.) m/z: 561.2(M+H)+. ¹H NMR (DMSO-d₆) δ: 8.51 (d, J=7.9 Hz, 1H), 8.10-8.01 (m, 2H),7.91 (s, 1H), 7.74 (dd, J=9.6, 6.5 Hz, 2H), 7.53 (dd, J=11.1, 5.4 Hz,1H), 5.04 (d, J=7.1 Hz, 2H), 4.49 (dd, J=8.3, 5.2 Hz, 1H), 3.87 (q,J=7.1 Hz, 1H), 3.63-3.49 (m, 2H), 3.28 (s, 3H), 2.35 (dd, J=11.3, 5.8Hz, 1H), 2.23 (ddd, J=14.5, 7.7, 3.9 Hz, 1H), 2.06 (dt, J=12.2, 6.9 Hz,2H), 1.82 (dt, J=13.5, 7.5 Hz, 3H), 1.72 (dd, J=7.4, 4.7 Hz, 1H), 1.62(q, J=7.9 Hz, 1H).

The compounds set forth in the following table were synthesizedfollowing the procedure described for Example 827 using known startingmaterial replacements as described.

TABLE 14 B-C Ring Amine Intermediate Structure, Name and Data Inter-mediate 37.0 Inter- mediate 5.0

((R)-N-((R)-(2,5-difluoro-4- (trifluoromethyl)phenyl)((1s,3S)-3-hydroxycyclobutyl)methyl)-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide LCMS-ESI (POS.) m/z:561.2 (M + H)+ Inter- mediate 37.1 Inter- mediate 5.0

((R)-N-((R)-(2,5-difluoro-4- (trifluoromethyl)phenyl)((1r,3R)-3-hydroxycyclobutyl)methyl)-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide LCMS-ESI (POS.) m/z:561.2 (M + H)+ Inter- mediate 37.0 Inter- mediate 31.3

(1R,3R,5R)-N-((R)-(2,5-difluoro-4- (trifluoromethyl)phenyl)((1s,3S)-3-hydroxycyclobutyl)methyl)-2-(2-(fluoromethyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3- carboxamideLCMS-ESI (POS.) m/z: 546.2 (M + H)+ Inter- mediate 37.1 Inter- mediate31.3

(1R,3R,5R)-N-((R)-(2,5-difluoro-4- (trifluoromethyl)phenyl)((1r,3R)-3-hydroxycyclobutyl)methyl)-2-(2-(difluoromethyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane- 3-carboxamideLCMS-ESI (POS.) m/z: 546.2 (M + H)+ Inter- mediate 21.2 Inter- mediate31.8

(1R,3R,5R)-N-((2,5-difluoro-4-(trifluoromethyl)phenyl)(5-oxopyrrolidin-3-yl)methyl)-2-(2-(trifluoromethyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane- 3-carboxamideLCMS-ESI (POS.) m/z: 577.2 (M + H)+

Example of Route AF:(1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)3-hydroxy-3-methylcyclobutyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 829)

Synthesis of(1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(3-oxocyclobutyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide

To a solution of(1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)((1s,3S)-3-hydroxycyclobutyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(0.32 g, 0.56 mmol) in DCM (4 mL) at 0 C was added Dess-Martinperiodinane (0.356 g, 0.84 mmol). The reaction was stirred for 15 minsat 0 C and then the solution was warmed to rt. The reaction wasmonitored by TLC analysis. After the completion of the reaction, thereaction was cooled to 0 C and then quenched with 2:1 sodiumthiosulfate-sodium bicabonate solution. The reaction was stirred untilthe phases became clear. The aq layer was extracted once with DCM andthe combined organic layer was dried, filtered, and concentrated andtaken through the next step without further purification (245 mg). ESI(pos.) m/z: 571.2 (M+H)⁺. ¹H NMR (DMSO-d₆) δ: 8.82 (d, J=8.3 Hz, 1H),8.18 (t, J=1.8 Hz, 1H), 8.05 (ddt, J=21.7, 7.8, 1.4 Hz, 2H), 7.87-7.75(m, 2H), 7.65 (dd, J=10.9, 5.7 Hz, 1H), 5.27 (t, J=8.4 Hz, 1H), 4.92(dd, J=11.4, 3.8 Hz, 1H), 3.31-3.22 (m, 4H), 3.16-3.06 (m, 1H),3.06-2.93 (m, 2H), 2.93-2.79 (m, 2H), 2.64-2.54 (m, 1H), 1.73 (ddd,J=15.3, 11.3, 5.1 Hz, 2H), 1.17 (td, J=5.0, 2.6 Hz, 1H), 0.77 (ddt,J=14.4, 8.6, 5.7 Hz, 1H).

Synthesis of(1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(3-hydroxy-3-methylcyclobutyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(Example 829)

A 8 mL vial was charged with(1R,3R,5R)—N—((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(3-oxocyclobutyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(200 mg, 0.35 mmol) and dissolved in THF (3 mL). The solution was cooledto 0 C and methyl magnesium bromide (0.23 mL, 0.701 mmol, 3M in ether)was subsequently added DROPWISE and stirred for 20 mins and analyzed byLCMS. The reaction was quenched with satd aq ammonium chloride andextracted with ethyl acetate. The combined organic layer were washedwith brine, dried, and concentrated under vacuo. The crude was purifiedby reverse phase HPLC using 10-100% acetonitrile/water over 40 minutes(phenomenex gemini c-18 5-micron column), providing the desired product(10 mg). ESI (pos.) m/z: 587.2 (M+H)+. ¹H NMR (Methanol-d₄) δ: 8.39 (t,J=1.8 Hz, 1H), 8.12 (ddd, J=8.0, 3.1, 1.3 Hz, 2H), 7.78 (t, J=7.8 Hz,1H), 7.52 (dd, J=9.5, 5.7 Hz, 1H), 7.35 (dd, J=10.7, 5.4 Hz, 1H), 5.06(dd, J=11.3, 4.0 Hz, 1H), 3.37 (s, 1H), 3.19 (s, 3H), 2.69 (ddd, J=13.7,11.5, 6.4 Hz, 1H), 2.29 (dq, J=10.0, 4.3, 3.8 Hz, 2H), 2.03 (dd, J=14.2,2.2 Hz, 1H), 1.99-1.86 (m, 3H), 1.81 (dq, J=9.0, 6.1 Hz, 1H), 1.31 (s,3H), 1.23 (td, J=5.4, 2.6 Hz, 1H), 0.90 (dt, J=8.8, 5.7 Hz, 1H).

All compounds shown in the below table were prepared using a syntheticroute as indicated, and their LCMS and NMR characterization are asshown.

LCMS-ESI (POS/NEG) Ex. m/z: Syn. # Structure Name (M + H)+ NMR Data Rte.1

LCMS-ESI (POS.) m/z: 575.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.28- 8.55 (m, 1 H), 7.39-8.00 (m, 8 H), 4.59-5.01 (m, 1 H), 4.34-4.56(m, 1 H), 4.02 (br dd,J = 8.69, 3.76 Hz, 2 H), 3.82- 3.89 (m, 2 H),3.41-3.64 (m, 3 H), 2.19-2.32 (m, 1 H), 1.69-1.93 (m, 4 H), 1.16-1.51(m, 1 H), −0.15-0.78 (m, 5 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-2-cyclopropyl-1-(4- (trifluoromethyl)phenyl)ethyl)-D-prolinamide 2

N-((R)-(4-chloro-2- fluorophenyl)(cyclopropyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- piperidinyl)carbonyl)-D-prolinamideLCMS-ESI (POS.) m/z: 552.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.35- 8.86 (m, 1 H), 7.40-7.47 (m, 1 H), 7.34-7.40 (m, 1 H), 7.25-7.31(m, 1 H), 4.45-4.51 (m, 1 H), 4.29- 4.43 (m, 1 H), 4.03-4.10 (m, 2 H),3.90-3.98 (m, 2 H), 3.79 (qt, J = 9.01, 6.08 Hz, 1 H), 3.34-3.59 (m, 4H), 2.67-2.88 (m, 2 H), 2.13-2.33 (m, 1 H), 1.97- 2.06 (m, 1 H),1.57-1.93 (m, 5 H), 1.33-1.56 (m, 2 H), 1.06-1.22 (m, 1 H), 0.49- 0.58(m, 1 H), 0.22-0.48 (m, 3 H) A 3

LCMS-ESI (POS.) m/z: 549.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.25- 8.53 (m, 1 H), 7.37-7.99 (m, 8 H), 4.31-4.86 (m, 2 H), 3.93-4.13(m, 2 H), 3.81-3.93 (m, 2 H), 3.44- 3.69 (m, 3 H), 2.17-2.32 (m, 1 H),1.40-1.93 (m, 5 H), 0.45-0.97 (m, 3 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)propyl)-D- prolinamide 4

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- LCMS-ESI (POS.) m/z:574.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.30- 8.82 (m, 1 H), 7.55(br d, J = 15.57 Hz, 3 H), 4.84- 5.07 (m, 1 H), 4.31-4.55 (m, 1 H),4.05-4.12 (m, 2 H), 3.91-3.98 (m, 2 H), 3.76-3.84 (m, 1 H), 3.31- 3.62(m, 4 H), 2.70-2.88 (m, 2 H), 2.60-2.68 (m, 1 H), 2.01-2.22 (m, 1 H),1.61-1.92 (m, 7 H), 1.34- 1.52 (m, 2 H), 0.80-0.97 (m, 3 H) Apiperidinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)propyl)-D-prolinamide 5

LCMS-ESI (POS.) m/z: 533.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.23-7.95 (m, 8 H), 6.15-7.17 (m, 1 H), 4.82- 4.95 (m, 1 H), 4.39-4.60(m, 2 H), 3.77-4.15 (m, 5 H), 3.36-3.45 (m, 1 H), 3.26-3.36 (m, 1 H),1.86- 1.95 (m, 1 H), 1.57-1.80 (m, 1 H), 0.70-0.95 (m, 1 H), 0.06-0.31(m, 1 H) C (1R,2R,5S)-3-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide 6

LCMS- APCI (NEG.) m/z: 569.2 (M − H) ¹H NMR (400 MHz, Methanol-d₄) δ ppm8.12 (s, 1 H), 8.01 (dd, J = 7.8, 14.8 Hz, 2 H), 7.81 (t, J = 7.7 Hz, 1H), 7.59-7.69 (m, 2 H), 7.52 (d, J = 8.0 Hz, 2 H), 5.12 (q, J = 7.1 Hz,1 H), 4.12 (td, J = 2.9, 8.7 Hz, 3 H), 3.94 (dd, J = 6.0, 8.5 Hz, 3 H),3.45-3.61 (m, 1 H), 2.82 (td, J = 7.9, 14.4, 14.9 Hz, 1 H), 2.32-2.54(m, 1 H), 1.53 (d, J = 7.0 Hz, 3 H). Q 1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-4,4-difluoro-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D- prolinamide 7

LCMS-ESI (POS.) m/z: 603.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.55- 8.69 (m, 1 H), 7.52-8.01 (m, 8 H), 5.03-5.36 (m, 1 H), 4.44-4.55(m, 1 H), 3.94-4.08 (m, 2 H), 3.81- 3.90 (m, 2 H), 3.43-3.66 (m, 3 H),2.62-2.95 (m, 2 H), 2.18-2.32 (m, 1 H), 1.71- 1.95 (m, 3 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-3,3,3-trifluoro-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide 8

LCMS-APCI (POS.) m/z: 557.2 (M + H)⁺ ¹H NMR (400 MHz, Methanol-d₄) δ ppm7.19- 8.20 (m, 8 H), 3.86-4.99 (m, 9 H), 3.44-3.58 (m, 1 H), 2.79-3.05(m, 1 H), 2.47-2.69 (m, 1 H). Q 1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-4,4-difluoro-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 9

LCMS-ESI (POS.) m/z: 588.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.25- 8.75 (m, 1 H), 7.52-7.6 5 (m, 3 H), 4.80-4.89 (m, 1 H), 4.59-4.60(m, 1 H), 4.35 (dd, J = 8.50, 3.83 Hz, 1 H), 4.04-4.08 (m, 2 H),3.91-3.98 (m, 2 H), 3.75-3.85 (m, 1 H), 3.30- 3.61 (m, 4 H), 2.69-2.88(m, 2 H), 2.60-2.67 (m, 1 H), 1.31-2.03 (m, 9 H), 0.66- 1.03 (m, 6 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-D- prolinamide 10

LCMS-ESI (POS.) m/z: 581.0 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52(br J = 8.29 Hz, 1 H), 7.55-7.94 (m, 7 H), 6.46- 6.48 (m, 1 H),4.82-4.95 (m, 1 H), 4.51-4.57 (m, 1 H), 4.02 (br dd, J = 8.76, 2.75 Hz,3 H), 3.42-3.63 (m, 4 H), 1.96-2.15 (m, 1 H), 1.62-1.86 (m, 4 H),0.47-1.02 (m, 6 H) A 1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-D-prolinamide 11

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((R)-cyclopropyl(4- LCMS-ESI (POS.) m/z: 568.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.32- 8.97 (m, 1 H), 7.63-7.73(m, 2 H), 7.49-7.60 (m, 2 H), 4.49 (br dd, J = 8.43, 2.98 Hz, 1 H), 4.27(br d, J = 8.17 Hz, 1 H), 4.06 (t, J = 7.79 Hz, 2 H), 3.92-3.97 (m, 2H), 3.75- 3.85 (m, 1 H), 3.25-3.58 (m, 4 H), 2.69-2.87 (m, 2 H),2.55-2.67 (m, 1 H), 1.63- 2.09 (m, 6 H), 1.36-1.54 (m, 2 H), 1.04-1.16(m, 1 H) 0.30- 0.58 (m, 4 H) A(trifluoromethyl)phenyl)methyl)-D-prolinamide 12

LCMS-ESI (POS.) m/z: 567.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.57(d, J = 7.79 Hz, 1 H), 7.42- 8.02 (m, 7 H), 4.65-5.10 (m, 1 H),4.33-4.58 (m, 1 H), 3.98-4.05 (m, 2 H), 3.85-3.92 (m, 2 H), 3.46- 3.69(m, 3 H), 2.18-2.30 (m, 1 H), 1.43-1.92 (m, 5 H), 0.54-0.96 (m, 3 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N- ((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)propyl)-D-prolinamide 13

LCMS-APCI (NEG.) m/z: 547.1 (M − H) ¹H NMR (400 MHz, Methanol-d₄) δ ppm7.05 (s, 0 H), 6.41-6.57 (m, 2 H), 6.21-6.41 (m, 2 H), 6.00 (dd, J =2.0, 8.5 Hz, 2 H), 5.79 (s, 1 H), 3.78 (s, 1 H), 3.54 (s, 1 H), 2.63(td, J = 2.2, 8.7 Hz, 2 H), 2.33-2.49 (m, 2 H), 1.90-2.13 (m, 2 H),0.57- 0.88 (m, 1 H), 0.19-0.51 (m, 2 H), − 0.20-0.15 (m, 6 H). Q(2R)-1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-(3,4-dichlorophenyl)ethyl)-2- piperidinecarboxamide 14

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-2-cyclopropyl-1-(4- LCMS-ESI (POS.) m/z:582.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.19- 8.72 (m, 1 H),7.60-7.74 (m, 2 H), 7.41-7.58 (m, 2 H), 4.81-5.03 (m, 1 H), 4.32-4.49(m, 1 H), 4.02- 4.08 (m, 2 H), 3.90-3.97 (m, 2 H), 3.70-3.82 (m, 1 H),3.26-3.44 (m, 1 H), 3.26-3.66 (m, 3 H), 2.69- 2.90 (m, 2 H), 2.58-2.67(m, 1 H), 1.62-2.11 (m, 7 H), 1.28-1.58 (m, 3 H), 0.56- 0.78 (m, 1 H),0.28-0.48 (m, 2 H), − 0.08-0.20 (m, 2H) A(trifluoromethyl)phenyl)ethyl)-D-prolinamide 15

(6R)-5-((3-((3-cyano-1- LCMS-APCI (POS.) m/z: 547.1 (M + H)⁺ ¹H NMR (400MHz, Methanol-d₄) δ ppm 8.16 (s, 1 H), 8.00 (ddd, J = 1.6, 6.8, 8.8 Hz,2 H), 7.79 (t, J = 7.7 Hz, 1 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.54 (d, J =8.1 Hz, 2 H), 4.79 (t, J = 7.6 Hz, 1 H), 4.61 (dd, J = 5.0, 15.8 Hz, 1H), 4.42- 4.56 (m, 1 H), 4.12 (td, J = 2.9, 8.8 Hz, 2 H), 3.88-3.94 (m,2 H), 3.77 (d, J = 10.1 Hz, 1 H), 3.46-3.58 (m, 1 H), 2.15 (qd, J = 7.5,12.6 Hz, 2 H), 0.50-0.68 (m, 4 H). Qazetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-5-azaspiro[2.4]heptane-6- carboxamide 16

LCMS-ESI (POS.) m/z: 553.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.53(d, J = 7.53 Hz, 1 H), 7.57-7.89 (m, 5 H), 7.39- 7.55 (m, 2 H), 5.00 (t,J = 7.01 Hz, 1 H), 4.49 (dd, J = 8.37, 5.26 Hz, 1 H), 3.91-4.11 (m, 5H), 3.47- 3.69 (m, 2 H), 2.19-2.28 (m, 1 H), 1.74-1.89 (m, 3 H),1.10-1.43 (m, 3 H) C 1-((3-((3-cyano-1-azetidinyl)sulfonyl)-5-fluorophenyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide 17

LCMS-ESI (POS.) m/z: 556.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.17- 8.72 (m, 1 H), 7.63-7.76 (m, 2 H), 7.44-7.54 (m, 2 H), 4.68-4.81(m, 1 H), 4.33-4.41 (m, 1 H), 4.03- 4.10 (m, 2 H), 3.90-3.99 (m, 2 H),3.76-3.85 (m, 1 H), 3.29-3.63 (m, 4 H), 2.70- 2.88 (m, 2 H), 2.60-2.68(m, 1 H), 1.61-2.16 (m, 8 H), 1.30-1.57 (m, 2 H), 0.76- 0.95 (m, 3 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide 18

LCMS-APCI (NEG.) m/z: 513.2 (M − H) ¹H NMR (400 MHz, Methanol-d₄) δ ppm8.47 (s, 1 H), 7.84-8.02 (m, 4 H), 7.69-7.84 (m, 2 H), 7.33 (d, J = 4.6Hz, 7 H), 5.23 (s, 1 H), 5.06 (d, J = 7.3 Hz, 2 H), 4.10 (td, J = 2.8,8.9 Hz, 4 H), 3.78- 3.98 (m, 4 H), 3.49 (s, 4 H), 2.12-2.34 (m, 2 H),1.82- 2.00 (m, 1H), 1.61-1.82 (m, 4 H), 1.40-1.61 (m, 9 H). Q(2R)-N-((1R)-1-(4-chlorophenyl)ethyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-2- piperidinecarboxamide 19

LCMS-ESI (POS.) m/z: 551.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.52- 8.73 (m, 1 H), 7.95 (br s, 1 H), 7.75-7.88 (m, 3 H), 7.70 (br d, J= 8.04 Hz, 2 H), 7.54 (br d, J = 6.62 Hz, 2 H), 5.05 (br s, 1 H),4.20-4.44 (m, 2 H), 3.52- 4.07 (m, 8 H), 3.10-3.49 (m, 2 H), 1.32-1.48(m, 3 H) C (3R)-4-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-3- morpholinecarboxamide 20

LCMS-ESI (POS.) m/z: 530.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.32- 8.69 (m, 1 H), 7.60 (dd, J = 9.28, 6.29 Hz, 1 H), 7.24-7.37 (m, 1H), 4.18- 4.54 (m, 3 H), 3.99-4.09 (m, 2 H), 3.86-3.98 (m, 2 H),3.75-3.83 (m, 1 H), 3.40-3.71 (m, 4 H), 2.62- 2.87 (m, 3 H), 1.86-2.33(m, 4 H), 1.37-1.81 (m, 4 H) AN-(4-chloro-2,5-difluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- piperidinyl)carbonyl)-D-prolinamide 21

1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-APCI (NEG.) m/z: 519.1 (M −H) ¹H NMR (400 MHz, Methanol-d₄) δ ppm 8.14 (t, J = 1.8 Hz, 1 H), 8.00(dt, J = 2.3, 8.2 Hz, 2 H), 7.80 (dd, J = 6.7, 9.0 Hz, 1 H), 7.56-7.68(m, 3 H), 7.52-7.58 (m, 2 H), 4.52- 4.68 (m, 2 H), 4.46 (d, J = 15.8 Hz,1 H), 4.11 (td, J = 2.5, 8.9 Hz, 2 H), 3.87- 3.99 (m, 3 H), 3.69 (dt, J= 6.8, 10.4 Hz, 1 H), 3.54 (dddd, J = 5.2, 7.9, 15.3, 18.1 Hz, 2 H),2.33-2.44 (m, 1 H), 1.91-2.05 (m, 3 H). Q 22

LCMS-ESI (POS.) m/z: 521.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.98-8.03 (m, 1 H), 7.91- 7.95 (m, 1 H), 7.80-7.85 (m, 1 H), 7.66-7.72(m, 1 H), 7.36- 7.44 (m, 2 H), 7.26-7.31 (m, 1 H), 7.14 (dd, J = 8.21,1.94 Hz, 1 H), 4.75 (dd, J = 7.57, 5.03 Hz, 1 H), 4.38-4.48 (m, 2 H),4.11-4.17 (m, 2 H), 4.02 (dd, J = 8.01, 6.71 Hz, 2 H), 3.57-3.67 (m, 1H), 3.44-3.52 (m, 1 H), 3.31-3.42 (m, 1 H), 2.44-2.54 (m, 1 H),2.06-2.20 (m, 2 H), 1.84-1.98 (m, 1 H) A 1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(3,4-dichlorobenzyl)-D-prolinamide 23

(1R,3R,5R)-2-(2-(ethylamino)-5-methylbenzoyl)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS-APCI(POS.) m/z: 520.2 (M + H)⁺ ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.76 (d, J =7.9 Hz, 1 H), 7.70 (d, J = 10.2 Hz, 1 H), 7.54- 7.65 (m, 2 H), 7.00-7.12(m, 2 H), 6.57 (d, J = 8.4 Hz, 1 H), 5.49 (t, J = 8.7 Hz, 1 H), 4.91 (d,J = 10.5 Hz, 1 H), 4.66 (t, J = 7.0 Hz, 1 H), 4.52 (t, J = 7.1 Hz, 1 H),4.42 (t, J = 6.0 Hz, 1 H), 4.23 (t, J = 6.0 Hz, 1 H), 3.00-3.14 (m, 3H), 2.19 (s, 3 H), 1.72 (dd, J = 13.2 Hz, 1 H), 1.56 (h, 1 H), 1.15 (t,J = 7.1 Hz, 2 H), 0.93 (s, 1 H), 0.63 (q, J = 5.9 Hz, 1 H). Q 24

LCMS-ESI (POS.) m/z: 535.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.21- 8.57 (m, 1 H), 7.70-8.03 (m, 4 H), 7.23-7.44 (m, 3 H), 5.05-5.14(m, 1 H), 4.52-4.60 (m, 1 H), 3.29- 4.10 (m, 10 H), 2.16-2.31 (m, 1 H),1.69-1.96 (m, 3 H) A N-((1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-D-prolinamide 25

LCMS-ESI (NEG.) m/z: 562.2 (M − H)⁻ 1H NMR (500 MHz, DMSO-d6) δ ppm8.54- 8.92 (m, 1 H), 7.65-7.71 (m, 2 H), 7.46 (br d, J = 8.17 Hz, 2 H),4.53-4.88 (m, 1 H), 4.31-4.49 (m, 2 H), 3.51-4.24 (m, 9 H), 2.74-3.03(m, 3 H), 2.55- 2.67 (m, 1 H), 2.32-2.43 (m, 1 H), 1.85-1.97 (m, 1 H),1.71 (br dd, J = 13.69, 3.18 Hz, 1 H), 1.31-1.55 (m, 2 H) M1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4,4-difluoro-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 26

LCMS-APCI (POS.) m/z: 568.2 (M + H)⁺ ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.95 (d, J = 7.2 Hz, 1 H), 7.62- 7.77 (m, 3 H), 7.52 (d, J = 2.2 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1 H), 7.03 (s, 1 H), 4.55-4.64 (m, 2 H), 3.16-3.26 (m, 2 H), 3.11 (s, 2 H), 2.17-2.29 (m, 2 H), 1.63- 1.81 (m, 4 H),1.17-1.28 (m, 2 H), 0.73-0.84 (m, 2 H), 0.57-0.64 (m, 1 H), 0.29- 0.52(m, 5 H). S 1-(2-(cyclopropylamino)-5-(methylsulfonyl)benzoyl)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D- prolinamide 27

LCMS-APCI (NEG.) m/z: 533.2 (M − H) ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s,1 H), 7.92 (d, J = 6.0 Hz, 1 H), 7.85 (s, 1 H), 7.76 (s, 2 H), 7.76 (d,J = 10.5 Hz, 1 H), 7.66 (d, J = 7.9 Hz, 2 H), 7.51 (d, J = 8.0 Hz, 2 H),4.84 (s, 1 H), 4.46 (d, J = 5.8 Hz, 2 H), 4.13 (t, J = 8.6 Hz, 2 H),3.93 (ddd, J = 8.7, 6.1, 3.1 Hz, 2 H), 3.83 (d, J = 13.8 Hz, 1 H),3.75-3.60 (m, 1 H), 3.37-3.16 (m, 1 H), 2.22 (d, J = 13.9 Hz, 1 H), 1.71(d, J = 39.4 Hz, 3 H), 1.53 (d, J = 3.6 Hz, 0 H), 1.58-1.45 (m, 2 H). Q(2R)-1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-piperidinecarboxamide,(2S)-1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-piperidinecarboxamide 28

LCMS-ESI (POS.) m/z: 610.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.24- 8.98 (m, 1 H), 7.66-7.81 (m, 2 H), 7.48-7.63 (m, 2 H), 5.16-5.31(m, 1 H), 4.21-4.43 (m, 1 H), 4.03- 4.14 (m, 2 H), 3.91-3.97 (m, 2 H),3.78-3.83 (m, 2 H), 3.30-3.63 (m, 4 H), 2.78-2.96 (m, 3 H), 2.59- 2.68(m, 1 H), 2.07-2.24 (m, 1 H), 1.58-1.97 (m, 5 H), 1.25-1.56 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-3,3,3-trifluoro-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide 29

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-fluoro-4- LCMS-ESI (POS.) m/z: 560.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.39- 8.81 (m, 1 H), 7.49-7.67(m, 3 H), 5.04-5.22 (m, 1 H), 4.27-4.53 (m, 1 H), 4.02-4.11 (m, 2 H),3.90- 3.98 (m, 2 H), 3.74-3.86 (m, 1 H), 3.51-3.61 (m, 3 H), 3.32-3.41(m, 1 H), 2.70-2.87 (m, 2 H), 2.15- 2.35 (m, 1 H), 1.95-2.14 (m, 1 H),1.63-1.93 (m, 5 H), 1.34-1.56 (m, 5 H) C(trifluoromethyl)phenyl)ethyl)-D-prolinamide 30

LCMS-ESI (POS.) m/z: 561.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.45- 8.68 (m, 1 H), 7.37-8.03 (m, 8 H), 4.26-4.60 (m, 2 H), 3.95-4.07(m, 2 H), 3.79-3.91 (m, 2 H), 3.43- 3.71 (m, 3 H), 2.15-2.35 (m, 1 H),1.65-1.95 (m, 3 H), −0.07-1.24 (m, 5 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N- ((R)-cyclopropyl(4-(trifluoromethyl)phenyl)methyl)-D-prolinamide 31

LCMS-ESI (POS.) m/z: 551.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.26- 8.57 (m, 1 H), 7.42-8.02 (m, 8 H), 4.92 (q, J = 6.31 Hz, 1 H),4.57 (br dd, J = 8.17, 4.80 Hz, 1 H), 3.26-4.07 (m, 10H), 2.16-2.29 (m,1 H), 1.64- 1.96 (m, 3 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N- ((1S)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide 32

LCMS-ESI (POS.) m/z: 546.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.39- 8.79 (m, 1 H), 7.68-7.79 (m, 1 H), 7.35 (br d, J = 12.07 Hz, 1 H),7.24-7.31 (m, 1 H), 4.25-4.55 (m, 3 H), 4.00-4.10 (m, 2 H), 3.88-3.98(m, 2 H), 3.74- 3.83 (m, 1 H), 3.35-3.70 (m, 4 H), 2.63-2.87 (m, 3 H),1.36-2.16 (m, 8 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide 33

LCMS-ESI (POS.) m/z: 558.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.22- 8.97 (m, 1 H), 7.31-7.74 (m, 3 H), 4.59-4.96 (m, 1 H), 4.19-4.59(m, 2 H), 3.29-4.15 (m, 10 H), 2.57- 3.00 (m, 3 H), 1.95-2.29 (m, 1 H),1.00-1.95 (m, 5 H), 0.58-0.87 (m, 1 H) C(1R,3R,5R)-2-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 34

(4R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-1-(2-(ethylamino)-5-methylbenzoyl)-4-hydroxy-D-prolinamide LCMS-APCI (POS.) m/z: 508.1 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (s, 1 H), 7.60-7.72 (m, 1 H),7.48 (dd, J = 6.3, 9.8 Hz, 1 H), 7.03 (d, J = 8.1 Hz, 1 H), 6.89 (s, 1H), 6.55 (d, J = 8.3 Hz, 1 H), 5.45 (d, J = 26.1 Hz, 2 H), 5.13 (s, 1H), 4.65 (s, 1 H), 4.32-4.55 (m, 3 H), 4.05-4.29 (m, 2 H), 3.42 (s, 2H), 3.15- 3.27 (m, 1 H), 3.05 (q, J = 6.8 Hz, 2 H), 2.42 (q, J = 7.2 Hz,2 H), 2.18 (s, 3 H), 1.58 (s, 1 H), 1.14 (t, J = 7.1 Hz, 3 H). Q 35

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((R)-cyclopropyl(2,5- LCMS-ESI (POS.) m/z: 604.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.34- 8.94 (m, 1 H), 7.48-7.80(m, 2 H), 4.31-4.57 (m, 2 H), 4.27-4.32 (m, 1 H), 4.01-4.07 (m, 2 H),3.87- 3.93 (m, 1 H), 3.73-3.82 (m, 1 H), 3.50-3.62 (m, 3 H), 3.26-3.46(m, 1 H), 2.57-2.87 (m, 3 H), 2.00- 2.29 (m, 1 H), 1.62-1.98 (m, 5 H),1.35-1.58 (m, 2 H), 1.09-1.24 (m, 1 H), 0.27-0.62 (m, 4 H) Adifluoro-4-(trifluoromethyl)phenyl)methyl)-D- prolinamide 36

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-3-hydroxy-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide LCMS-ESI (POS.) m/z: 572.2(M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58-7.68 (m, 2 H), 7.43(d, J = 8.19 Hz, 2 H), 7.35-7.40 (m, 1 H), 5.17- 5.25 (m, 1 H), 4.47(dd, J = 7.93, 2.85 Hz, 1 H), 4.06- 4.18 (m, 4 H), 3.57-3.83 (m, 6 H),3.44 (tt, J = 8.71, 6.53 Hz, 1 H), 3.00 (dd, J = 12.70, 11.04 Hz, 1 H),2.67-2.85 (m, 2 H), 2.14-2.32 (m, 2 H), 1.93-2.14 (m, 4 H), 1.77-1.89(m, 2 H), 1.53-1.75 (m, 3 H) A 37

LCMS-ESI (POS.) m/z: 561.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.59(d, J = 8.04 Hz, 1 H), 7.20-8.00 (m, 8 H), 4.08-4.60 (m, 2 H), 3.98-4.04 (m, 1 H), 3.82-3.94 (m, 2 H), 3.77-4.05 (m, 1 H), 3.44-3.71 (m, 3H), 2.23-2.37 (m, 1 H), 1.79- 2.00 (m, 3 H), 1.07-1.23 (m, 1 H),0.22-0.62 (m, 4 H) A 1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((S)-cyclopropyl(4- (trifluoromethyl)phenyl)methyl)-D-prolinamide 38

N-(3-chloro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- piperidinyl)carbonyl)-D-prolinamideLCMS-ESI (POS.) m/z: 562.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.61-7.66 (m, 1 H), 7.56 (br t, J = 5.86 Hz, 1 H), 7.37 (s, 1 H), 7.24(d, J = 7.98 Hz, 1 H), 4.60-4.65 (m, 1 H), 4.56 (dd, J = 15.70, 6.89 Hz,1 H), 4.33 (dd, J = 15.76, 5.29 Hz, 1 H), 4.06- 4.17 (m, 4 H), 3.72-3.83(m, 2 H), 3.53-3.66 (m, 2 H), 3.43 (tt, J = 8.69, 6.54 Hz, 1 H), 2.98(dd, J = 12.75, 10.99 Hz, 1 H), 2.65-2.83 (m, 2 H), 2.40-2.51 (m, 1 H),2.12-2.28 (m, 1 H), 2.01- 2.12 (m, 1 H), 1.77- 1.99 (m, 3 H), 1.63-1.73(m, 1 H), 1.48-1.59 (m, 1 H) A 39

N-((R)-(4-chloro-2,5- difluorophenyl)(cyclopropyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- piperidinyl)carbonyl)-D-prolinamideLCMS-ESI (POS.) m/z: 570.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.27- 8.88 (m, 1 H), 7.34-7.65 (m, 2 H), 5.57-5.58 (m, 1 H), 4.43-4.50(m, 1 H), 4.27-4.31 (m, 1 H), 4.01- 4.06 (m, 2 H), 3.88-3.95 (m, 2 H),3.72-3.81 (m, 1 H), 3.23-3.58 (m, 4 H), 2.77-2.84 (m, 1 H), 2.68 (s, 1H), 2.18-2.34 (m, 1 H), 1.99-2.17 (m, 1 H), 1.64-1.93 (m, 5 H), 1.32-1.54 (m, 2 H), 1.06-1.19 (m, 1 H), 0.26-0.61 (m, 4 H) A 40

LCMS-APCI (POS.) m/z: 594.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.97 (d, J = 6.7 Hz, 1 H), 7.61- 7.72 (m, 3 H), 7.01 (d, J = 6.0 Hz, 1H), 6.65 (d, J = 8.7 Hz, 1 H), 4.94-5.03 (m, 1 H), 4.43-4.52 (m, 1 H),3.89-4.01 (m, 2 H), 3.09 (s, 3 H), 1.80-1.90 (m, 2 H), 1.69 (dt, J =8.9, 16.9 Hz, 3 H), 1.52-1.62 (m, 2 H), 1.17-1.29 (m, 2 H), 0.67-0.76(m, 1 H), 0.53-0.67 (m, 2 H), 0.24- 0.53 (m, 4 H). S(1R,3R,5R)-2-(2-(cyclobutylamino)-5-(methylsulfonyl)benzoyl)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 41

1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide LCMS-APCI (NEG.) m/z: 533.2(M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm 8.11 (t, J = 1.8 Hz, 1 H),7.94- 8.05 (m, 2 H), 7.78 (q, J = 6.7, 7.3 Hz, 2 H), 7.63 (d, J =8.1 Hz,1 H), 7.52 (d, J = 8.1 Hz, 2 H), 5.10 (td, J = 4.9, 7.2 Hz, 1 H), 4.61(dd, J = 5.9, 8.2 Hz, 1 H), 4.11 (dd, J = 7.8, 9.6 Hz, 3 H), 3.88-3.99(m, 3 H), 3.63 (dt, J =6.8, 10.5 Hz, 1 H), 3.52 (dtd, J = 3.2, 6.4, 11.6Hz, 2 H), 2.33 (tdt, J = 6.7, 11.9, 14.2 Hz, 1 H), 1.86-1.98 (m, 3 H),1.52 (dd, J = 2.0, 7.1 Hz, 3 H). A 42

1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 539.0 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.99-8.05 (m, 1 H), 7.92-7.98(m, 1 H), 7.81- 7.86 (m, 1 H), 7.68-7.76 (m, 1 H), 7.49-7.56 (m, 1 H),7.37-7.45 (m, 1 H), 7.30-7.36 (m, 1 H), 7.26- 7.27 (m, 1 H), 4.72-4.80(m, 1 H), 4.51-4.63 (m, 2 H), 4.10-4.18 (m, 2 H), 3.99-4.07 (m, 2 H),3.58- 3.68 (m, 1 H), 3.44-3.54 (m, 1 H), 3.31-3.42 (m, 1 H), 2.38-2.49(m, 1 H), 2.09-2.19 (m, 2 H), 1.86- 1.99 (m, 1 H) A 43

N-(4-chlorobenzyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D- prolinamide LCMS-APCI (NEG.)m/z: 485.1 (M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm 8.13 (t, J = 1.8Hz, 1 H), 7.99 (dd, J = 1.8, 7.8 Hz, 2 H), 7.80 (t, J = 7.8 Hz, 1 H),7.27-7.36 (m, 4 H), 4.55- 4.67 (m, 1 H), 4.49 (d, J = 15.4 Hz, 1 H),4.32-4.43 (m, 1 H), 4.11 (t, J = 8.6 Hz, 2 H), 3.93 (dt, J = 5.8, 8.6Hz, 3 H), 3.53 (dddt, J = 4.5, 6.4, 10.9, 13.5 Hz, 2 H), 2.31-2.46 (m, 1H), 1.99- 2.06 (m, 2 H), 1.85-1.96 (m, 1 H). A 44

LCMS-APCI (POS.) m/z: 582.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.98 (d, J = 7.1 Hz, 1 H), 7.59- 7.75 (m, 4 H), 7.50 (d, J = 2.3 Hz, 1H), 6.99 (d, J = 6.0 Hz, 1 H), 6.66 (d, J = 8.9 Hz, 1 H), 4.53-4.66 (m,3 H), 3.90-4.01 (m, 2 H), 3.10 (s, 2 H), 1.63- 1.91 (m, 8 H), 1.19-1.29(m, 2 H), 0.56-0.66 (m, 2 H), 0.40-0.54 (m, 3 H), 0.30-0.40 (m, 2 H). S1-(2-(cyclobutylamino)-5- (methylsulfonyl)benzoyl)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D- prolinamide 45

LCMS-ESI (POS.) m/z: 577.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.24- 8.55 (m, 1 H), 7.35-8.02 (m, 8 H), 4.83-5.00 (m, 1 H), 4.35-4.50(m, 1 H), 3.92-4.07 (m, 2 H), 3.78- 3.90 (m, 2 H), 3.42-3.67 (m, 3 H),1.04-2.26 (m, 7 H), 0.63-0.97 (m, 6 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N- ((1R)-3-methyl-1-(4-(trifluoromethyl)phenyl)butyl)-D-prolinamide 46

LCMS-ESI (POS.) m/z: 499.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.14- 8.53 (m, 1 H), 7.69-8.01 (m, 4 H), 6.89-7.31 (m, 3 H), 4.80-5.18(m, 1 H), 4.22-4.56 (m, 1 H), 3.94- 4.10 (m, 2 H), 3.81-3.94 (m, 2 H),3.41-3.70 (m, 3 H), 2.15-2.32 (m, 4 H), 1.70-1.91 (m, 3 H), 0.99- 1.45(m, 3 H) A 1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-(2-fluoro-4-methylphenyl)ethyl)-D-prolinamide 47

LCMS-ESI (POS.) m/z: 585.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.07- 8.78 (m, 3 H), 5.21 (br t, J = 8.43 Hz, 1 H), 4.16- 4.50 (m, 1 H),4.00-4.12 (m, 2 H), 3.88-4.00 (m, 2 H), 3.75-3.86 (m, 1 H), 3.50-3.68(m, 4 H), 3.12- 3.28 (m, 2 H), 2.73-3.01 (m, 3 H), 2.58-2.68 (m, 1 H),1.58-2.24 (m, 7 H), 0.70-1.55 (m, 4 H) GN-((S)-3-azetidinyl(4-chloro-2,5-difluorophenyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 48

N-((1R)-1-(4-chloro-2,5-difluorophenyl)ethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- LCMS-ESI (POS.) m/z: 544.0(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.23- 8.76 (m, 1 H), 7.24-7.67(m, 2 H), 4.97-5.16 (m, 1 H), 4.21-4.57 (m, 1 H), 4.01-4.12 (m, 2 H),3.88- 3.99 (m, 2 H), 3.75-3.86 (m, 1 H), 3.49-3.69 (m, 3 H), 3.21-3.44(m, 3 H), 2.70-2.90 (m, 2 H), 2.60- 2.69 (m, 1 H), 2.03-2.38 (m, 1 H),1.60-1.96 (m, 5 H), 1.27-1.59 (m, 5 H) Apiperidinyl)carbonyl)-D-prolinamide 49

1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)-D- prolinamide LCMS-ESI (POS.)m/z: 535.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.36-8.09 (m, 5H), 7.30-7.35 (m, 1 H), 7.16- 7.28 (m, 1 H), 7.13-7.28 (m, 1 H),6.76-6.78 (m, 1 H), 6.50-6.77 (m, 1 H), 5.27-5.37 (m, 1 H), 4.67- 4.77(m, 1 H), 4.01-4.22 (m, 4 H), 3.60-3.72 (m, 1 H), 3.44-3.55 (m, 1 H),3.33-3.44 (m, 1 H), 2.26- 2.40 (m, 1 H), 2.07-2.23 (m, 2 H), 1.86-1.99(m, 1 H), 1.50-1.60 (m, 1 H), 1.34-1.42 (m, 1 H), 1.56 (d, J = 7.01 Hz,2 H) A 50

LCMS-APCI (POS.) m/z: 568.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.88 (d, J = 7.2 Hz, 1 H), 7.60- 7.74 (m, 3 H), 6.79 (d, J = 8.9 Hz, 1H), 6.66 (t, J = 5.0 Hz, 1 H), 4.93-5.02 (m, 1 H), 4.54 (t, J = 7.8 Hz,1 H), 3.19 (dd, J = 5.3, 7.3 Hz, 2 H), 3.09 (s, 2 H), 1.79 (d, J = 13.9Hz, 1 H), 1.53-1.63 (m, 1 H), 1.16- 1.25 (m, 1 H), 1.13 (t, J = 7.2 Hz,2 H), 0.73-0.82 (m, 1 H), 0.53-0.65 (m, 2 H), 0.29-0.53 (m, 3 H). S(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-(ethylamino)-5-(methylsulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide 51

LCMS-ESI (POS.) m/z: 512.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.29-8.77 (m, 1 H), 7.46- 7.58 (m, 1 H), 7.20-7.33 (m, 1 H), 7.06-7.15(m, 1 H), 4.17-4.53 (m, 3 H), 3.99-4.12 (m, 2 H), 3.86- 3.99 (m, 2 H),3.72-3.85 (m, 1 H), 3.24-3.70 (m, 4 H), 2.71-2.87 (m, 2 H), 2.58-2.70(m, 1 H), 2.03- 2.25 (m, 1 H), 1.66-1.99 (m, 5 H), 1.34-1.55 (m, 2 H) AN-(4-chloro-3-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 52

LCMS-ESI (POS.) m/z: 619.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.46- 8.79 (m, 1 H), 7.69-8.00 (m, 6 H), 7.42-7.62 (m, 2 H), 4.25-4.57(m, 2 H), 3.96-4.05 (m, 2 H), 3.86- 3.94 (m, 2 H), 3.57 (br dd, J =6.94, 5.77 Hz, 1 H), 3.42-3.54 (m, 2 H), 2.18- 2.29 (m, 1 H), 1.67-1.87(m, 3 H), 0.86-1.18 (m, 1 H), −0.10-0.55 (m, 4 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((R)-cyclopropyl(4-(pentafluoro-lambda~6~-sulfanyl)phenyl)methyl)-D-prolinamide 53

LCMS-ESI (POS.) m/z: 539.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.50- 8.68 (m, 1 H), 7.56-7.94 (m, 4 H), 7.17-7.53 (m, 2 H), 4.32-4.55(m, 3 H), 3.88-4.29 (m, 6 H), 3.45- 3.72 (m, 2 H), 2.20-2.32 (m, 1 H),1.77-1.98 (m, 3 H) C 1-((3-((3-cyano-1-azetidinyl)sulfonyl)-5-fluorophenyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 54

(3R)-4-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-fluoro-4- LCMS-ESI (POS.) m/z: 598.2(M + Na)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.52-8.72 (m, 1 H), 7.51-7.68(m, 3 H), 5.06-5.28 (m, 1 H), 4.51-4.77 (m, 1 H), 4.24-4.47 (m, 1 H),3.24-4.10 (m, 11 H), 2.68-2.98 (m, 3 H), 2.51-2.58 (m, 1 H), 1.76-1.92(m, 1 H), 1.28-1.75 (m, 6 H) C (trifluoromethyl)phenyl)ethyl)-3-morpholinecarboxamide 55

LCMS-ESI (POS.) m/z: 489.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.45- 8.68 (m, 1 H), 7.63-8.05 (m, 4 H), 6.70-7.13 (m, 3 H), 4.10-4.56(m, 3 H), 3.81-4.08 (m, 4 H), 3.44- 3.69 (m, 3 H), 2.19-2.33 (m, 1 H),1.77-1.97 (m, 3 H) A 1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-(3,5-difluorobenzyl)-D-prolinamide 56

(4S)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-fluoro-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 546.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.59 (s, 1 H), 7.57 (s, 1 H),7.38 (s, 1 H), 7.37 (s, 1 H), 5.26-5.43 (m, 1 H), 4.73 (t, J = 7.79 Hz,1 H), 4.52-4.59 (m, 1 H), 4.39-4.46 (m, 1 H), 4.07-4.15 (m, 4 H), 4.00(br dd, J = 18.94, 12.98 Hz, 1 H), 3.78 (br t, J = 12.85 Hz, 2 H),3.57-3.72 (m, 1 H), 3.39-3.50 (m, 1 H), 2.88-2.97 (m, 1 H), 2.66- 2.83(m, 3 H), 2.34-2.44 (m, 1 H), 1.88 (br d, J = 12.85 Hz, 1 H), 1.80 (brd, J = 13.10 Hz, 1 H), 1.58-1.70 (m, 1 H), 1.50-1.58 (m, 1 H), 1.37-1.48(m, 1 H) M 57

LCMS-ESI (POS.) m/z: 517.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.20-8.48 (m, 1 H), 7.20-8.03 (m, 8 H), 4.82-4.87 (m, 1 H), 4.56 (br d,J = 5.19 Hz, 1 H), 4.30-4.36 (m, 1 H), 3.85-4.07 (m, 4 H), 3.31- 3.72(m, 5 H), 2.18-2.29 (m, 1 H), 1.62-1.92 (m, 3 H) AN-((1S)-1-(4-chlorophenyl)-2-hydroxyethyl)-1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-D- prolinamide 58

LCMS-ESI (POS.) m/z: 542.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.46-8.82 (m, 1 H), 7.43- 7.97 (m, 7 H), 4.13-4.67 (m, 2 H), 3.41-3.65(m, 2 H), 2.56-2.69 (m, 6 H), 2.16-2.33 (m, 1 H), 1.58- 1.94 (m, 3 H),1.14-1.30 (m, 1 H), −0.06-0.64 (m, 4 H) A N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide 59

LCMS-APCI (POS.) m/z: 527.2 (M + H)⁺ ¹H NMR (Methanol-d₄) δ: 7.74-7.59(m, 2 H), 7.59-7.42 (m, 2 H), 4.70- 4.52 (m, 1 H), 4.52-4.40 (m, 2 H),4.12-3.89 (m, 1 H), 3.89-3.68 (m, 3 H), 3.39-3.31 (m, 3 H), 2.96- 2.65(m, 7 H), 2.34-2.22 (m, 1 H), 2.19-1.88 (m, 4 H), 1.90-1.76 (m, 1 H),1.72-1.49 (m, 2 H) R 1-(((3S)-1-((cis-3-cyanocyclobutyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 60

LCMS-ESI (POS.) m/z: 542.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.28(br t, J = 5.77 Hz, 1 H), 7.27-7.60 (m, 3 H), 4.20-4.56 (m, 3 H), 4.00-4.15 (m, 2 H), 3.87-3.98 (m, 2 H), 3.74-3.86 (m, 1 H), 3.42-3.73 (m, 4H), 2.72-2.91 (m, 2 H), 2.59- 2.71 (m, 1 H), 2.30-2.38 (m, 3 H),2.04-2.23 (m, 1 H), 1.64-2.01 (m, 5 H), 1.33-1.56 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methyl-4-(trifluoromethyl)benzyl)-D-prolinamide 61

LCMS-APCI (POS.) m/z: 582.2 (M + H)⁺ ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.91 (d, J = 6.8 Hz, 1 H), 7.55- 7.74 (m, 4 H), 6.80 (d, J = 9.6 Hz, 1H), 6.58 (d, J = 7.5 Hz, 1 H), 4.93-5.02 (m, 1 H), 4.50 (t, J = 7.8 Hz,1 H), 3.74 (q, J = 6.5 Hz, 2 H), 3.09 (s, 3 H), 1.83 (d, J = 14.1 Hz, 2H), 1.50-1.62 (m, 2 H), 1.17-1.29 (m, 2 H), 1.11 (dd, J = 6.3, 14.4 Hz,4 H), 0.69-0.77 (m, 1 H), 0.25-0.65 (m, 6 H). S(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(5-(methylsulfonyl)-2-(2-propanylamino)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 62

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 546.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.36-7.45 (m, 2 H), 7.29-7.34(m, 1 H), 4.43- 4.62 (m, 3 H), 4.04-4.15 (m, 4 H), 3.77 (br d, J = 12.20Hz, 2 H), 3.50-3.70 (m, 2 H), 3.37-3.48 (m, 1 H), 2.87-3.03 (m, 1 H),2.64-2.84 (m, 2 H), 2.41 (ddd, J = 9.44, 6.52, 3.37 Hz, 1 H), 2.12-2.23(m, 2 H), 2.04 (dddd, J = 12.91, 9.76, 6.46, 6.29 Hz, 1 H), 1.78-1.97(m, 3 H), 1.50-1.71 (m, 2 H) C 63

N-(2-chloro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- piperidinyl)carbonyl)-D-prolinamideLCMS-ESI (POS.) m/z: 562.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.60-7.68 (m, 1 H), 7.43-7.58 (m, 3 H), 4.43- 4.65 (m, 3 H), 4.06-4.18(m, 4 H), 3.72-3.82 (m, H), 3.52- 3.64 (m, 2 H), 3.43 (tt, J = 8.71,6.53 Hz, 1 H), 2.98 (dd, J = 12.70, 11.04 Hz, 1 H), 2.65-2.83 (m, 2 H),2.44 (ddt, J = 12.21, 6.19, 3.03, 3.03 Hz, 1 H), 2.10- 2.23 (m, 1 H),1.99-2.10 (m, 1 H), 1.78-1.97 (m, 3 H), 1.62-1.75 (m, 1 H), 1.49-1.59(m, 1 H) A 64

LCMS-ESI (POS.) m/z: 505.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.63(t, J = 6.03 Hz, 1 H), 7.66- 8.04 (m, 4 H), 7.51 (d, J = 8.04 Hz, 1 H),7.17 (s, 2 H), 4.28-4.54 (m, 3 H), 4.11 (br dd, J = 17.00, 5.71 Hz, 1H), 3.84-3.94 (m, 3 H), 3.57-3.71 (m, 2 H), 3.40-3.52 (m, 1 H),2.18-2.34 (m, 1 H), 1.73-1.97 (m, 3 H) AN-(4-chloro-3-fluorobenzyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D- prolinamide 65

(2R)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-piperidinecarboxamide LCMS-ESI (POS.) m/z:564.0 (M + Na)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.65-8.70* (m, 1 H),8.38 (br t, J = 6.23 Hz, 1 H), 7.69 (br d, J = 8.17 Hz, 2 H), 7.42-7.49(m, 2 H), 5.05 (br d, J = 4.93 Hz, 1 H), 4.69-4.74* (m, 1 H), 4.29-4.42(m, 2 H), 4.02-4.08 (m, 2 H), 3.89- 3.95 (m, 2 H), 3.72-3.87 (m, 2 H),3.50-3.65 (m, 2 H), 3.25-3.30 (m, 1 H), 2.60-2.96 (m, 3 H), 2.25- 2.32*(m, 1 H), 2.14 (br dd, J = 13.56, 2.66 Hz, 1 H), 1.48-1.89 (m, 6 H),1.17- 1.46 (m, 3 H). Spectrum appears as 2:1 mixture of rotamers,*denotes resolved minor rotamer peaks. M 66

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane- 3-carboxamideLCMS-APCI (POS.) m/z: 539.1 (M + H)⁺ ¹H NMR (400 MHz, Methanol-d₄) δ ppm8.34 (t, J = 1.7 Hz, 1 H), 8.13 (dt, J = 1.3, 7.7 Hz, 1 H), 8.07 (ddd, J= 1.1, 1.9, 7.9 Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.39 (dd, J = 6.1,9.4 Hz, 1 H), 7.27 (dd, J = 6.3, 9.4 Hz, 1 H), 5.57 (d, J = 10.2 Hz, 1H), 4.99 (dd, J = 4.3, 11.4 Hz, 1 H), 4.84 (dd, J = 6.5, 7.6 Hz, 1 H),4.67 (dd, J = 6.4, 7.8 Hz, 1 H), 4.60 (t, J = 6.2 Hz, 1 H), 4.38 (t, J =0.8, 12.5 Hz, 1 H), 3.51 (dddd, J = 5.0, 6.3, 7.8, 16.6 Hz, 1 H), 3.37(s, 2 H), 3.24- 3.32 (m, 3 H), 2.67 (dddd, J = 1.1, 6.5, 11.7, 13.3 Hz,1 H), 1.90 (dd, J = 4.2, 13.5 Hz, 1 H), 1.76-1.85 (m, 1 H), 1.22-1.31(m, 4 H), 0.90 (dtd, J = 1.1, 5.7, 9.0 Hz, 1 H). A 67

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 528.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.72* (t, J = 5.81 Hz, 1 H), 8.36 (t, J = 6.07 Hz, 1 H), 7.65- 7.71 (m,2 H), 7.45 (br d, J = 7.85 Hz, 2 H), 4.28-4.50 (m, 3 H), 4.03-4.10 (m, 2H), 3.90-3.98 (m, 2 H), 3.75-3.83 (m, 1 H), 3.34-3.68 (m, 4 H),2.73-2.87 (m, 2 H), 2.64-2.70 (m, 1 H), 2.28-2.35* (m, 1 H), 2.18-2.26*(m, 1 H), 2.05- 2.15 (m, 1 H), 1.68- 1.98 (m, 5 H), 1.37- 1.54 (m, 2 H).Spectrum appears as 2:1 mixture of rotamers, *denotes resolved minorrotamer peaks. M 68

LCMS-ESI (POS.) m/z: 584.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.12-8.75 (m, 1 H), 7.60- 7.75 (m, 2 H), 7.42-7.56 (m, 2 H), 4.82-4.97(m, 1 H), 4.30-4.43 (m, 1 H), 4.02-4.10 (m, 2 H), 3.91- 3.98 (m, 2 H),3.75-3.84 (m, 1 H), 3.32-3.63 (m, 4 H), 2.87 (s, 2 H), 2.02- 2.22 (m, 1H), 1.30-1.92 (m, 11 H), 0.80-0.95 (m, 6 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-3-methyl-1-(4-(trifluoromethyl)phenyl)butyl)-D-prolinamide 69

N-((1R)-1-(4-chloro-3-fluorophenyl)ethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide LCMS-ESI (POS.) m/z: 526.2 (M + H)⁺1H NMR (500 MHz, DMSO-d6) δ ppm 8.64* (d, J = 7.66 Hz, 1 H), 8.19-8.27(m, 1 H), 7.48-7.56 (m, 1 H), 7.29 (br d, J = 11.16 Hz, 1 H), 7.11-7.16(m, 1 H), 4.83- 4.94 (m, 1 H), 4.41-4.49* (m, 1 H), 4.19-4.28 (m, 1 H),4.02-4.09 (m, 2 H), 3.90- 3.98 (m, 2 H), 3.76-3.84 (m, 1 H), 3.29-3.64(m, 4 H), 2.74-2.84 (m, 2 H), 2.61- 2.68 (m, 1 H), 2.26-2.35* (m, 1 H),2.16-2.26* (m, 1 H), 2.02-2.15 (m, 1 H), 1.64-1.91 (m, 5 H), 1.37-1.54(m, 2 H), 1.34-1.37* (m, 3 H), 1.30-1.34 (m, 3 H). Spectrum appears as3:1 mixture of rotamers, *de- notes resolved minor rotamer peaks. C 70

N-(4-chloro-2-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide LCMS-ESI(POS.) m/z: 512.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.28-7.38 (m, 1 H), 7.20-7.26 (m, 1 H), 7.04- 7.13 (m, 2 H), 4.56 (dd, J= 8.04, 1.95 Hz, 1 H), 4.35- 4.46 (m, 2 H), 4.06-4.14 (m, 4 H),3.69-3.79 (m, 2 H), 3.51-3.62 (m, 2 H), 3.39- 3.47 (m, 1 H), 2.89-3.01(m, 1 H), 2.65-2.80 (m, 2 H), 2.35-2.46 (m, 1 H), 2.09- 2.27 (m, 1 H),1.98-2.07 (m, 1 H), 1.77-1.95 (m, 3 H), 1.49-1.71 (m, 2 H) A 71

N-((1R)-1-(4-chlorophenyl)ethyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D- LCMS-APCI (NEG.) m/z: 499.1 (M− H) ¹H NMR (400 MHz, Methanol-d₄) δ ppm 8.05-8.18 (m, 1 H), 7.92- 8.04(m, 2 H), 7.74-7.80 (m, 1 H), 7.32 (s, 4 H), 5.02 (td, J = 5.9, 8.3, 9.4Hz, 1 H), 4.58 (dd, J = 5.8, 8.3 Hz, 1 H), 4.07-4.13 (m, 2 H), 3.90-3.96(m, 2 H), 3.47-3.58 (m, 2 H), 2.26- 2.37 (m, 1 H), 1.85-1.99 (m, 3 H),1.49 (d, J = 7.1 Hz, 3 H). A prolinamide 72

1-(((3S)-1((3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 581.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (br d, J = 8.04 Hz, 2 H),7.44 (br s, 1 H), 7.35 (d, J = 8.04 Hz, 2 H), 4.60 (br d, J = 6.49 Hz, 1H), 4.37-4.55 (m, 2 H), 4.12-4.26 (m, 5 H), 3.89-3.98 (m, H), 3.78 (brd, J = 12.46 Hz, 3 H), 3.54-3.64 (m, 2 H), 2.91- 3.05 (m, 4 H),2.66-2.89 (m, 2 H), 2.45 (ddd, J = 9.28, 6.29, 3.37 Hz, 2 H), 2.09-2.27(m, 1 H), 1.99- 2.09 (m, 1 H), 1.74-1.96 (m, 3 H), 1.45-1.72 (m, 4 H) M73

1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide LCMS-ESI (POS.) m/z: 562.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.54- 8.80 (m, 1 H), 7.51-7.66(m, 3 H), 5.03-5.23 (m, 1 H), 4.22-4.37 (m, 1 H), 4.08-4.16 (m, 2 H),3.99 (td, J = 8.14, 6.16 Hz, 2 H), 3.88-3.95 (m, 1 H), 3.77-3.86 (m, 1H), 3.25- 3.64 (m, 5 H), 2.89-3.11 (m, 2 H), 2.03-2.28 (m, 2 H),1.58-1.90 (m, 3 H), 1.34-1.43 (m, 3 H) C 74

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-(3- (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 525.1 (M +H)⁺ ¹H NMR (400 MHz, Methanol-d₄) δ ppm 8.39 (t, J = 1.6 Hz, 1 H),8.09-8.15 (m, 2 H), 7.79 (t, 1 H), 7.39 (dd, J = 6.1, 9.4 Hz, 1 H), 7.27(dd, J = 6.3, 9.4 Hz, 1 H), 5.57 (d, J = 10.2 Hz, 1 H), 4.99 (dd, J =4.2, 11.4 Hz, 1 H), 4.84 (dd, J = 6.5, 7.6 Hz, 1 H), 4.67 (dd, J = 6.5,7.8 Hz, 1 H), 4.60 (t, J = 6.2 Hz, 1 H), 4.38 (t, 1 H), 3.46- 3.56 (m, 1H), 3.37 (s, 1 H), 3.19 (s, 3 H), 2.67 (dddd, J = 1.1, 6.5, 11.7, 13.5Hz, 1 H), 1.91 (dd, 1 H), 1.76- 1.85 (m, 1 H), 1.27 (td, J = 2.6, 5.3Hz, 1 H), 0.91 (dtd, J = 1.1, 5.7, 9.0 Hz, 1 H). A 75

LCMS-ESI (POS.) m/z: 535.2 (M + Na)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δppm 7.36-8.24 (m, 8 H), 4.77-5.12 (m, 2 H), 4.46- 4.73 (m, 1 H),3.98-4.17 (m, 4 H), 3.70-3.85 (m, 1 H), 3.45-3.64 (m, 1 H), 3.26-3.42(m, 1 H), 3.15 (s, 2 H), 3.03 (s, 1 H), 1.76-2.49 (m, 4 H) C1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-methyl-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 76

1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(2-fluoro-4-methylbenzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 485.2 (M + H)⁺ 1H NMR(500 MHz, CHLOROFORM-d) δ ppm 8.03-8.09 (m, 1 H), 8.00-8.09 (m, 1 H),7.96- 8.03 (m, 1 H), 7.95-8.00 (m, 1 H), 7.84-7.93 (m, 1 H), 7.68-7.79(m, 1 H), 7.21-7.29 (m, 1 H), 7.03- 7.12 (m, 1 H), 6.88-7.01 (m, 2 H),4.69-4.82 (m, 1 H), 4.47-4.61 (m, 2 H), 4.12-4.22 (m, 2 H), 4.03- 4.11(m, 2 H), 3.58-3.73 (m, 1 H), 3.45-3.56 (m, 1 H), 3.31-3.45 (m, 1 H),2.32-2.50 (m, 4 H), 2.11- 2.24 (m, 2 H), 1.87-2.00 (m, 1 H) A 77

LCMS-ESI (POS.) m/z: 564.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.60 (t, J = 7.27 Hz, 2 H), 7.28-7.42 (m, 2 H), 7.09 (br d, J = 5.71 Hz,1 H), 4.40-4.56 (m, 3 H), 4.00-4.19 (m, 6 H), 3.83 (br d, J = 12.98 Hz,1 H), 3.55-3.76 (m, 3 H), 3.31-3.50 (m, 1 H), 2.94- 3.14 (m, 3 H),2.82-2.94 (m, 1 H), 1.89-2.54 (m, 6 H) M1-((-1-((3-cyano-1-azetidinyl)sulfonyl)-5,5-difluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 78

LCMS-ESI (POS.) m/z: 542.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.14- 8.67 (m, 1 H), 7.17-7.53 (m, 3 H), 4.97-5.10 (m, 1 H), 4.24-4.56(m, 1 H), 3.98-4.12 (m, 2 H), 3.89- 3.98 (m, 2 H), 3.74-3.86 (m, 1 H),3.27-3.67 (m, 6 H), 2.55-2.89 (m, 3 H), 1.21-2.33 (m, 9 H) AN-((1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 79

LCMS-APCI (POS.) m/z: 556.2 (M + H)⁺ ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.92 (d, J = 7.5 Hz, 1 H), 7.61-7.75 (m, 3 H), 7.53 (s, 1 H), 6.78 (d, J= 8.9 Hz, 1 H), 6.61 (t, 1 H), 4.56-4.64 (m, 2 H), 3.13- 3.31 (m, 5 H),3.10 (s, 2 H), 2.19-2.30 (m, 2 H), 1.73 (s, 3 H), 1.19-1.28 (m, 1 H),1.14 (t, J = 7.1 Hz, 3 H), 0.56-0.65 (m, 1 H), 0.44-0.52 (m, 1 H),0.32-0.43 (m, 2 H). S N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-(ethylamino)-5-(methylsulfonyl)benzoyl)-D-prolinamide 80

methyl ((3-(((1R,3R,5R)-3-(((R)-cyclopropyl(2,5- difluoro-4- LCMS-ESI(POS.) m/z: 601.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.35-8.79 (m,1 H), 8.18 (s, 1 H), 7.94-8.10 (m, 2 H), 7.65-7.87 (m, 2 H), 7.36-7.64(m, 1 H), 4.47- 5.06 (m, 4 H), 3.52-4.19 (m, 3 H), 3.23 (td, J = 6.16,2.47 Hz, 1 H), 2.52- 2.76 (m, 1 H), 1.51-1.83 (m, 2 H), 1.06-1.40 (m, 6H), −0.24-0.98 (m, 7 H) C (trifluoromethyl)phenyl)methyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2- yl)carbonyl)phenyl)sulfonyl)acetate 81

N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(5-(methylsulfonyl)-2-(2-propanylamino)benzoyl)-D- LCMS-APCI (POS.) m/z:570.2 (M + H)⁺ ¹H NMR (400 MHz, Methanol-d₄) δ ppm 7.76 (dd, J = 2.4,8.9 Hz, 1 H), 7.68 (dd, J = 2.2 Hz, 2 H), 7.52 (d, J = 8.3 Hz, 1 H),7.45 (d, J = 10.6 Hz, 1 H), 6.85 (d, J = 8.9 Hz, 1 H), 4.68-4.73 (m, 1H), 4.60 (d, J = 6.9 Hz, 1 H), 3.80 (p, J = 6.4 Hz, 1 H), 3.39-3.56 (m,2 H), 3.07 (s, 3 H), 2.37 (q, J = 7.2 Hz, 1 H), 1.88 (s, 3 H), 1.31 (s,3 H), 1.23 (dd, J = 6.3, 11.6 Hz, 5 H), 0.84-0.96 (m, 1 H), 0.67-0.75(m, 1 H), 0.51- 0.62 (m, 2 H), 0.41-0.49 (m, 1 H). S prolinamide 82

1-(((3S,4R)-1-((3-cyano-1-azetidinyl)sulfonyl)-4-methyl-3-piperidinyl)carbonyl)-N-(4- LCMS-ESI (POS.) m/z: 542.2 (M + H)⁺1H NMR (400 MHz, CHLOROFORM-d) δ 7.51-7.65 (m, 2 H), 7.32- 7.47 (m, 3H), 4.55-4.69 (m, 1 H), 4.36-4.55 (m, 2 H), 4.02-4.19 (m, 4 H),3.53-3.63 (m, 2 H), 3.35- 3.53 (m, 3 H), 3.23-3.35 (m, 1 H), 3.00-3.14(m, 1 H), 2.79-2.93 (m, 1 H), 2.37-2.51 (m, 1 H), 2.12-2.30 (m, 2 H),1.63-2.10 (m, 4 H), 0.70- 0.98 (m, 3 H)(trifluoromethyl)benzyl)-D-prolinamide 83

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-(3-fluoro-5-(methylsulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS-APCI (POS.) m/z: 543.1 (M + H)⁺ ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.67 (d, J = 8.1 Hz, 1 H), 8.04 (t, J = 1.5 Hz, 1 H), 7.98 (ddd, J =1.5, 2.5, 8.0 Hz, 1 H), 7.77-7.85 (m, 1 H), 7.67 (dd, J = 6.2, 9.5 Hz, 1H), 7.44 (dd, J = 6.3, 9.7 Hz, 1 H), 5.41 (t, J = 9.0 Hz, 1 H), 4.87(dd, J = 3.7, 11.4 Hz, 1 H), 4.63 (dd, J = 6.3, 7.7 Hz, 1 H), 4.51 (dd,J = 6.3, 7.8 Hz, 1 H), 4.37 (t, J = 6.2 Hz, 1 H), 4.20 (t, J = 6.2 Hz, 1H), 3.34 (s, 3 H), 3.31(d, J = 1.8 Hz, 1 H), 2.57 (dt, J = 6.0, 11.8 Hz,1 H), 1.65-1.82 (m, 2 H), 1.16 (td, J = 2.6, 5.1 Hz, 1 H), 0.68-0.85 (m,1 H). Q 84

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide LCMS-ESI (POS.) m/z: 542.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.71* (d, J = 7.01 Hz, 1 H),8.34 (d, J = 7.91 Hz, 1 H), 7.65- 7.72 (m, 2 H), 7.49 (t, J = 7.22 Hz, 2H), 4.89-5.01 (m, 1 H), 4.42-4.50* (m, 1 H), 4.23-4.33 (m, 1 H),4.02-4.09 (m, 2 H), 3.90- 3.96 (m, 2 H), 3.75-3.85 (m 1 H), 3.50-3.62(m, 3 H), 3.28-3.42 (m, 1 H), 2.73-2.86 (m, 2 H), 2.61-2.67 (m, 1 H),2.26-2.35* (m, 1 H), 2.16- 2.26* (m, 1 H), 2.03-2.14 (m, 1 H), 1.65-1.91(m, 5 H), 1.39-1.54 (m, 2 H), 1.33- 1.39 (m, 3 H). Spectrum appears as2:1 mix- ture of rotamers, *denotes resolved minor rotamer peaks. C 85

LCMS-ESI (POS.) m/z: 549.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.25-8.49 (m, 1 H), 7.15- 8.00 (m, 8 H), 4.57-4.85 (m, 1 H), 4.42 (s, 1H), 3.80-4.05 (m, 4 H), 3.57- 3.68 (m, 2 H), 3.45-3.54 (m, 1 H),2.21-2.34 (m, 1 H), 1.59-1.96 (m, 5 H), 0.74-0.95 (m, 3 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1S)-1-(4-(trifluoromethyl)phenyl)propyl)-D- prolinamide 86

LCMS-APCI (NEG.) m/z: 547.1 (M − H) ¹H NMR (400 MHz, Methanol-d₄) δ ppm7.85-8.01 (m, 2 H), 7.73- 7.83 (m, 0 H), 7.41-7.59 (m, 2 H), 7.28 (s, 1H), 5.21 (s, 1 H), 5.01 (qd, J = 2.1, 7.2 Hz, 1 H), 4.01- 4.17 (m, 2 H),3.82-3.97 (m, 2 H), 3.39-3.62 (m, 2 H), 3.34 (s, 1 H), 2.21 (s, 1 H),1.90 (s, 1 H), 1.61- 1.81 (m, 2 H), 1.52-1.61 (m, 1 H), 1.47 (d, J = 7.1Hz, 3 H). Q (2R)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1S)-1-(3,4-dichlorophenyl)ethyl)-2- piperidinecarboxamide 87

LCMS-ESI (POS.) m/z: 504.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.19-8.67 (m, 1 H), 7.15- 7.27 (m, 1 H), 6.89-7.04 (m, 2 H), 4.16-4.51(m, 3 H), 3.99-4.12 (m, 2 H), 3.85-3.98 (m, 2 H), 3.73- 3.83 (m, 1 H),3.41-3.71 (m, 4 H), 2.61-2.89 (m, 3 H), 2.04-2.34 (m, 4 H), 1.65- 1.99(m, 5 H), 1.34-1.56 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-4- methylbenzyl)-D-prolinamide 88

LCMS-ESI (POS.) m/z: 558.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.15-8.71 (m, 1 H), 7.44-7.74 (m, 4 H), 4.83- 4.92 (m, 1 H), 4.35 (brdd, J = 8.56, 4.02 Hz, 1 H), 4.03-4.11 (m, 2 H), 3.90- 3.98 (m, 2 H),3.76-3.86 (m, 1 H), 3.31-3.68 (m, 6 H), 2.73-2.89 (m, 2 H), 2.61-2.68(m, 1 H), 1.62- 2.37 (m, 7 H), 1.34-1.56 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide 89

LCMS-ESI (POS.) m/z: 577.2 (M + Na)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δppm 7.30-8.08 (m, 9 H), 7.13 (br d, J = 7.01 Hz, 1 H), 5.19-5.32 (m, 1H), 4.57 (br t, J = 8.04 Hz, 1 H), 3.59 (br d, J = 12.98 Hz, 1 H),3.11-3.34 (m, 2 H), 2.06-2.49 (m, 6 H), 1.50-1.95 (m, 6 H), 1.18- 1.43(m, 9 H), 0.35-0.74 (m, 5 H) C (2R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(propylsulfonyl)benzoyl)-2-piperidinecarboxamide 90

(1R,2R,5S)-3-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-3- azabicyclo[3.1.0]hexane-2-carboxamideLCMS-ESI (POS.) m/z: 540.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.54-7.69 (m, 2 H), 7.32-7.47 (m, 2 H), 7.00-7.19 (m, 1 H), 4.57- 4.65(m, 1 H), 4.48-4.60 (m, 1 H), 4.34-4.46 (m, 1 H), 4.33-4.68 (m, 1 H),4.01-4.19 (m, 4 H), 3.64- 3.80 (m, 4 H), 3.35-3.46 (m, 1 H), 2.87-2.97(m, 1 H), 2.70-2.82 (m, 1 H), 2.54-2.66 (m, 1 H), 1.71- 1.97 (m, 4 H),1.53-1.63 (m, 1 H), 1.32-1.46 (m, 1 H), 0.75-0.92 (m, 1 H), 0.09-0.25(m, 1 H) C 91

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,4-dichlorobenzyl)-D- prolinamide LCMS-ESI(POS.) m/z: 528.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.28-7.48 (m, 3 H), 7.06-7.12 (m, 1 H), 4.54- 4.63 (m, 1 H), 4.23-4.50(m, 2 H), 4.04-4.17 (m, 4 H), 3.71-3.81 (m, 2 H), 3.51- 3.70 (m, 2 H),3.39-3.48 (m, 1 H), 2.91-3.01 (m, 1 H), 2.67-2.85 (m, 3 H), 2.38- 2.46(m, 1 H), 2.16-2.26 (m, 1 H), 1.98-2.12 (m, 1 H), 1.80-1.98 (m, 3 H),1.50-1.73 (m, 2 H) C 92

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-(cyclopropylsulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS-ESI (POS.) m/z: 535.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.28- 8.67 (m, 1 H), 7.22-8.20 (m, 6 H), 4.93 (dd, J = 11.29, 3.50 Hz, 1H), 4.04- 4.56 (m, 1 H), 3.15-3.80 (m, 1 H), 2.85-2.99 (m, 1 H),2.52-2.59 (m, 1 H), 1.62- 1.80 (m, 1 H), 1.56 (br dd, J = 8.56, 5.45 Hz,1 H), 1.00-1.27 (m, 6 H), −0.24- 0.96 (m, 5 H) H 93

2-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4- LCMS-ESI(POS.) m/z: 569.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.97 (t, J =6.77 Hz, 1 H), 8.11 (br s, 1 H), 8.01 (br d, J = 7.66 Hz, 1 H),7.83-7.96 (m, 2 H), 7.72 (br s, 1 H), 7.53-7.68 (m, 2 H), 7.41- 7.51 (m,2 H), 7.22-7.41 (m, 3 H), 5.77 (br s, 1 H), 5.02 (br d, J = 14.01 Hz, 1H), 4.74 (br d, J = 13.62 Hz, 1 H), 4.45-4.52 (m, 1 H), 4.41 (br d, J =5.71 Hz, 1 H), 3.96-4.12 (m, 2 H), 3.84-3.96 (m, 2 H), 3.17 (s, 1 H) I(trifluoromethyl)benzyl)-2,3-dihydro-1H-isoindole- 1-carboxamide 94

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-(3-((2-hydroxyethyl)sulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS-APCI (POS.) m/z: 555.1 (M + H)⁺ ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.67 (d, J = 8.2 Hz, 1 H), 8.16 (t, J = 1.7 Hz, 1 H), 7.96-8.05 (m, 2H), 7.77 (t, J = 7.8 Hz, 1 H), 7.67 (dd, J = 6.3, 9.4 Hz, 2 H), 7.45(dd, J = 6.3, 9.7 Hz, 1 H), 5.41 (t, J = 8.9 Hz, 1 H), 4.83-4.93 (m, 2H), 4.63 (dd, J = 6.3, 7.7 Hz, 1 H), 4.46-4.54 (m, 1 H), 4.33-4.41 (m, 2H), 4.20 (t, J = 6.2 Hz, 1 H), 3.71 (q, J = 5.9 Hz, 2 H), 3.51 (t, J =6.2 Hz, 2 H), 3.20-3.30 (m, 1 H), 1.72 (dd, J = 3.6, 13.3 Hz, 2 H), 1.17(dd, J = 2.6, 5.1 Hz, 3 H), 0.72-0.86 (m, 2 H). Q 95

LCMS-APCI (NEG.) m/z: 556.1 (M − H) ¹H NMR (400 MHz, Methanol-d₄) δ ppm8.70 (s, 1 H), 8.14 (s, 1 H), 7.96-8.07 (m, 4 H), 7.75-7.84 (m, 2 H),4.69 (d, J = 15.9 Hz, 1 H), 4.50 (d, J = 15.8 Hz, 1 H), 4.13 (td, J =3.0, 8.3 Hz, 3 H), 3.95 (dd, J = 6.0, 8.5 Hz, 3 H), 3.52 (tt, J = 6.1,8.8 Hz, 1 H), 2.78-2.96 (m, 1 H), 2.48-2.65 (m, 1 H). Q1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-4,4-difluoro-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-D-prolinamide 96

LCMS-APCI (NEG.) m/z: 547.2 (M − H) ¹H NMR (400 MHz, Methanol-d₄) ppm7.40- 8.03 (m, 8 H), 4.36-4.84 (m, 3 H), 4.05-4.16 (m, 2 H), 3.88-3.98(m, 2 H), 3.11-3.68 (m, 3 H), 2.25- 2.44 (m, 1 H), 1.26-2.10 (m, 7 H). Q(2)-1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-azepanecarboxamide 97

LCMS-ESI (POS.) m/z: 538.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.12-8.71 (m, 1 H), 7.23-7.60 (m, 4 H), 4.88- 5.09 (m, 1 H), 4.32-4.54(m, 1 H), 4.01-4.12 (m, 2 H), 3.88-4.00 (m, 2 H), 3.71-3.87 (m, 1 H),3.43- 3.68 (m, 6 H), 3.15-3.27 (m, 3 H), 2.59-2.90 (m, 3 H), 2.01-2.31(m, 1 H), 1.64-1.99 (m, 5 H), 1.29- 1.58 (m, 2 H) AN-(-1-(4-chlorophenyl)-2-methoxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide 98

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-methylphenyl)ethyl)-D-prolinamide LCMS-ESI (POS.) m/z: 506.2 (M + H)⁺ 1HNMR (500 MHz, DMSO-d6) δ ppm 8.24 (d, J = 7.79 Hz, 1 H), 7.12-7.29 (m, 1H), 6.89- 7.06 (m, 2 H), 5.79-5.80 (m, 1 H), 4.96-5.22 (m, 1 H),4.26-4.51 (m, 1 H), 4.01-4.13 (m, 2 H), 3.89- 3.98 (m, 2 H), 3.74-3.85(m, 1 H), 3.48-3.61 (m, 3 H), 3.28-3.42 (m, 1 H), 2.69- 2.87 (m, 2 H),2.57-2.69 (m, 1 H), 2.24-2.31 (m, 3 H), 1.98-2.22 (m, 1 H), 1.60- 1.93(m, 5 H), 1.37-1.57 (m, 2 H), 1.23-1.37 (m, 3 H) A 99

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,4-dichlorobenzyl)-D- prolinamide LCMS-ESI(POS.) m/z: 528.0 (M + H)⁺ additional 1H count due to H₂O overlap 1H NMR(400 MHz, CHLORO- FORM-d) δ ppm 7.44 (br t, J = 5.75 Hz, 1 H), 7.39 (dd,J = 7.93, 1.61 Hz, 1 H), 7.26 (dd, J = 7.67, 1.55 Hz, 1 H), 7.15-7.20(m, 1 H), 4.53-4.64 (m, 2 H), 4.42-4.50 (m, 1 H), 4.07- 4.14 (m, 4 H),3.73-3.80 (m, 2 H), 3.53-3.60 (m, 2 H), 3.38-3.48 (m, 1 H), 2.98 (dd, J= 12.70, 11.04 Hz, 1 H), 2.64-2.82 (m, 2 H), 2.40-2.48 (m, 1 H),2.08-2.22 (m, 1 H), 1.99- 2.08 (m, 1 H), 1.78-1.96 (m, 3 H), 1.45-1.72(m, 3 H) A 100

LCMS-ESI (POS.) m/z: 507.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.47-8.70 (m, 1 H), 7.60- 8.04 (m, 4 H), 7.36-7.46 (m, 1 H), 6.64-7.12(m, 1 H), 4.15-4.54 (m, 3 H), 3.83-4.07 (m, 4 H), 3.45- 3.69 (m, 3 H),2.21-2.31 (m, 1 H), 1.75-1.98 (m, 3 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-(2,3,5-trifluorobenzyl)-D-prolinamide 101

LCMS-APCI (POS.) m/z: 596.2 (M + H)⁺ ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.87 (d, J = 6.9 Hz, 1 H), 7.52-7.72 (m, 3 H), 7.04 (d, J = 9.0 Hz, 1H), 6.49 (s, 1 H), 4.96 (dd, J = 3.1, 11.3 Hz, 1 H), 4.49 (t, J = 7.8Hz, 1 H), 3.09 (s, 2 H), 1.80 (dd, J = 16.1 Hz, 1 H), 1.52-1.62 (m, 1H), 1.33 (s, 4 H), 1.15-1.25 (m, 1 H), 0.69- 0.80 (m, 1 H), 0.57-0.69(m, 1 H), 0.26-0.49 (m, 2 H). S(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-((2-methyl-2-propanyl)amino)-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 102

LCMS-APCI (POS.) m/z: 503.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm7.12-8.30 (m, 8 H), 6.56- 6.90 (m, 1 H), 3.88-4.67 (m, 7 H), 3.39-3.84(m, 3 H), 2.30-2.46 (m, 1 H), 1.86-2.13 (m, 3 H). A 1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(difluoromethyl)benzyl)-D-prolinamide 103

1-(((1R,4R,6R)-2-((3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[2.2.1]hept-6-yl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z:558.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.28-7.48 (m, 4 H),4.42- 4.58 (m, 3H), 4.10-4.20 (m, 3 H), 4.03-4.10 (m, 2 H), 3.54-3.68(m, 2 H), 3.41 (tt, J = 6.32, 8.81 Hz, 1 H), 3.27 (td, J = 3.03, 8.66Hz, 1 H), 3.12 (dd, J = 5.29, 8.71 Hz, 1 H), 3.07 (d, J = 8.71 Hz, 1 H),2.67 (br s, 1 H), 2.40 (tdd, J = 3.11, 6.39, 12.37 Hz, 1 H), 2.10-2.23(m, 1 H), 1.98-2.08 (m, 1 H), 1.77- 1.97 (m, 4 H), 1.67 (br d, J = 10.26Hz, 1 H) M 104

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)-D- prolinamide LCMS-ESI (POS.)m/z: 542.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.28-7.45 (m, 2H), 7.13-7.25 (m, 1 H), 7.11- 7.30 (m, 2 H), 6.46-6.76 (m, 1 H),5.15-5.26 (m, 1 H), 4.48-4.58 (m, 1 H), 4.01-4.19 (m, 4 H), 3.70- 3.84(m, 2 H), 3.52-3.67 (m, 2 H), 3.37-3.49 (m, 1 H), 2.91-3.06 (m, 1 H),2.67-2.86 (m, 2 H), 2.25- 2.34 (m, 1 H), 2.08-2.21 (m, 1 H), 1.96-2.08(m, 2 H), 1.80-1.96 (m, 2 H), 1.56-1.76 (m, 2 H), 1.51- 1.56 (m, 1 H),1.37-1.50 (m, 2 H), 1.37-1.55 (m, 3 H) A 105

LCMS-ESI (POS.) m/z: 535.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.18- 8.51 (m, 1 H), 6.98-8.02 (m, 7 H), 4.84-4.91 (m, 1 H), 4.52-4.59(m, 1 H), 3.36-4.15 (m, 10 H), 2.16- 2.34 (m, 1 H), 1.73-2.02 (m, 3 H) AN-((1R)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-D-prolinamide 106

1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-methylbenzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 467.2 (M + H)⁺ 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.99-8.04 (m, 1 H), 7.91-7.97 (m, 1 H),7.82- 7.88 (m, 1 H), 7.66-7.74 (m, 1 H), 7.13-7.24 (m, 4 H), 6.98 (br t,J = 5.18 Hz, 1 H), 4.69-4.74 (m, 1 H), 4.45 (dd, J = 8.58, 5.83 Hz, 2H), 4.09- 4.16 (m, 2 H), 4.03 (d, J = 6.84 Hz, 2 H), 4.01 (s, 1 H) ,3.60-3.69 (m, 1 H), 3.43- 3.53 (m, 1 H), 3.35 (tt, J = 8.75, 6.54 Hz, 1H), 2.38- 2.47 (m, 1 H), 2.11-2.24 (m, 2 H), 1.87-1.97 (m, 1 H),1.84-2.26 (m, 1 H) A 107

LCMS-ESI (POS.) m/z: 568.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.25- 8.79 (m, 1 H), 7.55-7.77 (m, 4 H), 4.29-4.46 (m, 2 H), 4.05-4.09(m, 2 H), 3.87-3.94 (m, 2 H), 3.74- 3.83 (m, 1 H), 3.44-3.65 (m, 4 H),3.16-3.17 (m, 1 H), 2.70-2.91 (m, 2 H), 2.57-2.67 (m, 1 H), 2.08- 2.26(m, 1 H), 1.66-1.94 (m, 5 H), 1.12-1.53 (m, 3 H), 0.29-0.65 (m, 4 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((S)-cyclopropyl(4-(trifluoromethyl)phenyl)methyl)-D-prolinamide 108

LCMS-APCI (POS.) m/z: 492.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.80 (d, J = 7.3 Hz, 1 H), 7.57- 7.76 (m, 3 H), 7.01 (dd, J = 2.1, 8.5Hz, 1 H), 6.88 (s, 1 H), 6.54 (d, J = 8.5 Hz, 1 H), 5.49 (s, 1 H), 4.51-4.66 (m, 2 H), 3.15-3.27 (m, 1 H), 2.99-3.11 (m, 2 H), 2.17 (s, 4 H),1.61-1.78 (m, 3 H), 1.17-1.27 (m, 1 H), 1.12 (t, J = 7.1 Hz, 3 H), 0.59(s, 1 H), 0.32-0.53 (m, 3 H). Q N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-(ethylamino)-5-methylbenzoyl)-D-prolinamide 109

LCMS-ESI (POS.) m/z: 544.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.56-7.66 (m, 2 H), 7.34-7.44 (m, 2 H), 6.23- 6.69 (m, 1 H), 4.93 (d, J= 3.37 Hz, 1 H), 4.41-4.68 (m, 3 H), 4.05-4.17 (m, 4 H), 3.94-4.01 (m, 1H), 3.72- 3.88 (m, 2 H), 3.47-3.72 (m, 4 H), 3.36-3.47 (m, 1 H),2.91-3.11 (m, 1 H), 2.72-2.90 (m, 2 H), 1.37-1.94 (m, 4 H) M(3R)-4-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-3-morpholinecarboxamide 110

(4S)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-1-(2-(ethylamino)-5-methylbenzoyl)-4-hydroxy-D-prolinamide LCMS-APCI (POS.) m/z: 508.2 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (d, J = 8.3 Hz, 1 H), 7.66 (dd,J = 6.2, 9.4 Hz, 1 H), 7.47 (dd, J = 6.2, 9.8 Hz, 1 H), 7.04 (d, J = 8.3Hz, 1 H), 6.91 (s, 1 H), 6.56 (d, J = 8.4 Hz, 1 H), 5.38-5.57 (m, 2 H),5.03 (d, J = 3.1 Hz, 1 H), 4.65 (t, J = 7.0 Hz, 1 H), 4.48-4.61 (m, 2H), 4.43 (t, J = 6.1 Hz, 1 H), 4.22 (d, J = 6.1 Hz, 2 H), 3.57 (dd, J =3.7, 10.9 Hz, 1 H), 3.41 (dt, J = 6.5, 14.0 Hz, 1 H),2.98-3.18 (m, 3 H),2.18 (s, 3 H), 2.02-2.12 (m, 1 H), 1.15 (t, J = 7.1 Hz, 3 H). Q 111

N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)- D-prolinamide LCMS-APCI(POS.) m/z: 513.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.22 (t,J = 1.6 Hz, 1 H), 8.10 (ddd, J = 1.1, 1.9, 7.9 Hz, 1 H), 7.96 (dt, J =1.3, 7.9 Hz, 1 H), 7.75 (t, J = 7.7 Hz, 1 H), 7.39 (dd, J = 6.1, 9.5 Hz,1 H), 7.31 (dd, J = 6.3, 9.4 Hz, 1 H), 5.64 (d, J = 10.4 Hz, 1 H),4.64-4.72 (m, 2 H), 4.50- 4.58 (m, 2 H), 4.41 (t, 1 H), 3.75 (dp, J =4.8, 9.5 Hz, 1 H), 3.65 (dt, J = 7.2, 10.2 Hz, 1 H), 3.48-3.58 (m, 2 H),2.27- 2.40 (m, 1 H), 1.95- 2.05 (m, 1 H), 1.82- 1.95 (m, 3 H). A 112

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-((2-hydroxyethyl)sulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS-APCI (POS.) m/z: 539.1 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.63 (d, J = 7.7 Hz, 1 H), 8.14- 8.17 (m, 1 H), 8.02 (ddt, J = 1.3, 7.8,14.0 Hz, 2 H), 7.77 (t, J = 7.8 Hz, 1 H), 7.60-7.69 (m, 1 H), 7.50 (dd,J = 6.3, 9.8 Hz, 1 H), 4.90-4.98 (m, 1 H), 4.87 (t, J = 5.4 Hz, 1 H),4.51 (t, J = 7.9 Hz, 1 H), 4.36 (t, J = 5.1 Hz, 1 H), 3.70 (q, J = 5.9Hz, 2 H), 3.50 (t, J = 6.1 Hz, 2 H), 3.23 (dt, J = 3.2, 6.3 Hz, 1 H),1.71 (td, J = 5.4, 13.8 Hz, 3 H), 1.14-1.21 (m, 1 H), 1.09-1.14 (m, 1H), 0.74 (dt, J = 5.2, 10.4 Hz, 2 H), 0.54 (d, J = 8.2 Hz, 1 H), 0.46(d, J = 8.6 Hz, 2 H), 0.34 (d, J = 3.7 Hz, 2 H). Q 113

LCMS-ESI (POS.) m/z: 533.0 (M + Na)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.62 (br s, 1 H), 7.44-8.09 (m, 6 H), 4.35-5.26 (m, 2 H), 4.12 (br s, 1H), 3.32-3.45 (m, 1 H), 3.27 (br s, 3 H), 2.03-2.22(m, 1 H), 1.12- 1.77(m, 6 H), 0.25-0.66 (m, 4 H) C (2R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2-piperidinecarboxamide 114

LCMS-ESI (POS.) m/z: 508.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.54(br d, J = 8.04 Hz, 1 H), 7.06-7.96 (m, 7 H), 3.82- 4.53 (m, 2 H),3.40-3.68 (m, 2 H), 2.58-2.69 (m, 6 H), 2.20-2.37 (m, 1 H), 1.67-1.98(m, 3 H), 1.11- 1.22 (m, 1 H), −0.19-0.67 (m, 4 H) A N-((R)-(4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide 115

(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3- (trifluoromethyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 533.1 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (d, J = 7.5 Hz, 1 H), 7.99 (d,J = 7.7 Hz, 1 H), 7.95 (s, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.72-7.81(m, 2 H), 7.60 (dd, J = 5.6, 11.0 Hz, 1 H), 4.95 (dd, J = 3.6, 11.4 Hz,1 H), 4.53 (t, J = 7.9 Hz, 1 H), 3.24 (td, J = 2.5, 6.2 Hz, 1 H), 2.58(dt, J = 6.4, 12.0 Hz, 1 H), 1.74 (dd, J = 3.6, 13.6 Hz, 1 H), 1.64-1.71(m, 1 H), 1.16-1.25 (m, 1 H), 1.04- 1.12 (m, 1 H), 0.74 (dt, J = 5.3,9.8 Hz, 1 H), 0.53-0.62 (m, 1 H), 0.41-0.50 (m, 1 H), 0.37 (s, 2 H). Q116

1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 548.2 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.41-7.52 (m, 1 H), 7.35-7.40 (m, 1H), 7.31 (d, J = 9.85 Hz, 1 H), 7.20 (br t, J = 5.75 Hz, 1 H), 4.60-4.80(m, 1 H), 4.45-4.59 (m, 2 H), 4.13- 4.21 (m, 5 H), 4.00 (td, J = 2.80,11.30 Hz, 1 H), 3.82 (ddd, J = 4.04, 8.06, 10.50 Hz, 1 H), 3.64-3.75 (m,2 H), 3.42-3.57 (m, 3 H), 3.18 (dd, J = 9.64, 12.75 Hz, 1 H), 3.04 (ddd,J = 3.32, 10.88, 12.44 Hz, 1 H), 2.36- 2.45 (m, 1 H), 2.07-2.21 (m, 1H), 1.88-2.05 (m, 2 H) C 117

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((R)-cyclopropyl(4- LCMS-ESI (POS.) m/z : 626.0(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.33- 8.96 (m, 1 H), 7.43-7.95(m, 4 H), 4.40-4.53 (m, 1 H), 4.24 (br t, J = 8.17 Hz, 1 H), 4.02-4.11(m, 2 H), 3.89-3.99 (m, 2 H), 3.74-3.85 (m, 1 H), 3.33- 3.61 (m, 4 H),2.64-2.83 (m, 1 H), 2.07-2.28 (m, 2 H), 1.63-1.94 (m, 6 H), 1.35-1.52(m, 2 H), 1.07- 1.17 (m, 1 H), 0.29-0.61 (m, 4 H) A(pentafluoro-lambda-6~-sulfanyl)phenyl)methyl)- D-prolinamide 118

LCMS-APCI (POS.) m/z: 584.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.82 (d, J = 7.6 Hz, 1 H), 7.87 (d, J = 2.3 Hz, 1 H), 7.59- 7.74 (m, 3H), 6.78-6.91 (m, 2 H), 4.93-5.01 (m, 1 H), 4.80 (t, J = 5.3 Hz, 1 H),4.59 (t, J = 8.0 Hz, 1 H), 3.58 (p, J = 5.5 Hz, 2 H), 3.20-3.30 (m, 2H), 3.18 (s, 1 H), 3.09 (s, 2 H), 1.73 (dd, J = 3.3, 13.6 Hz, 2 H),1.54-1.65 (m, 1 H), 1.13-1.27 (m, 2 H), 0.87- 0.99 (m, 1 H), 0.62-0.69(m, 1 H), 0.54-0.62 (m, 1 H), 0.41-0.54 (m, 1 H), 0.29-0.41 (m, 2 H). S(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-((2-hydroxyethyl)amino)-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 119

LCMS-ESI (POS.) m/z: 508.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.10-8.60 (m, 1 H), 7.03- 7.35 (m, 3 H), 4.12-4.51 (m, 3 H), 4.01-4.12(m, 2 H), 3.89-3.99 (m, 2 H), 3.73-3.87 (m, 1 H), 3.39- 3.69 (m, 4 H),2.60-2.84 (m, 3 H), 2.07-2.36 (m, 4 H), 1.66-2.01 (m, 5 H), 1.26-1.57(m, 2 H) A N-(4-chloro-2-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 120

LCMS-ESI (POS.) m/z: 517.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.24- 8.58 (m, 1 H), 7.72-8.01 (m, 4 H), 7.31-7.56 (m, 4 H), 6.85-7.12(m, 1 H), 4.69-5.02 (m, 1 H), 4.56 (s, 1 H), 3.99-4.07 (m, 2 H),3.87-3.90 (m, 2 H), 3.48- 3.65 (m, 3 H), 2.19-2.29 (m, 1 H), 1.74-1.94(m, 3 H), 1.09-1.43 (m, 3 H) A 1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-(4-(difluoromethyl)phenyl)ethyl)-D-prolinamide 121

LCMS-ESI (POS.) m/z: 523.1 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.38- 8.66 (m, 1 H), 7.75-7.97 (m, 4 H), 7.47-7.74 (m, 4 H), 5.01 (br s,1 H), 3.56- 4.25 (m, 6 H), 2.80-2.96 (m, 3 H), 1.29-1.46 (m, 6 H) C3-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-(((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)benzamide 122

LCMS-APCI (POS.) m/z: 539.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm6.87-7.52 (m, 1 H), 6.63- 6.78 (m, 2 H), 6.49-6.57 (m, 1 H), 5.99-6.45(m, 4 H), 3.90-4.18 (m, 1 H), 3.53-3.65 (m, 1 H), 2.45- 3.34 (m, 8 H),2.14-2.30 (m, 1 H), 1.11-1.45 (m, 2 H). Q (4R)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-4-fluoro-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 123

1-((1-((3-cyano-1-azetidinyl)sulfonyl)-1H-pyrazol-4-yl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D- prolinamide LCMS-ESI(POS.) m/z: 511.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 8.31-8.45(m, 1 H), 8.18-8.26 (m, 1 H), 7.55- 7.64 (m, 2 H), 7.38-7.45 (m, 2 H),7.30-7.38 (m, 1 H), 4.75-4.85 (m, 1 H), 4.51-4.64 (m, 1 H), 4.38- 4.51(m, 5 H), 3.82-3.92 (m, 1 H), 3.71-3.82 (m, 1 H), 3.47-3.58 (m, 1 H),2.43-2.55 (m, 1 H), 2.22- 2.36 (m, 1 H), 1.97-2.16 (m, 2 H) M 124

LCMS-ESI (Pos.) m/z: 517.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.38(d, J = 8.30 Hz, 1 H), 7.58-8.04 (m, 4 H), 6.78- 7.16 (m, 3 H),4.32-4.82 (m, 2 H), 3.99-4.09 (m, 2 H), 3.86-3.90 (m, 2 H), 3.41-3.68(m, 3 H), 3.29- 3.30 (m, 1 H), 2.19-2.32 (m, 1 H), 1.74 (br dd, J =5.71, 2.72 Hz, 5 H), 0.39-0.97 (m, 3 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-1-(3,5-difluorophenyl)propyl)-D-prolinamide 125

LCMS-ESI (POS.) m/z: 512.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.80-8.99 (m, 1 H), 8.43-8.67 (m, 1 H), 7.95-8.10 (m, 2 H), 7.47-7.70(m, 2 H), 4.45 (br s, 2 H), 3.32- 3.55 (m, 4 H), 3.01-3.15 (m, 1 H),1.97-2.25 (m, 1 H), 1.10-1.81 (m, 6 H), 0.26-0.65 (m, 4 H) C(2R)-N-((R)-(4-chloro-2,5- difluorophenyl)(cyclopropyl)methyl)-1-((6-(methylsulfonyl)-3-pyridinyl)carbonyl)-2- piperidinecarboxamide 126

LCMS-APCI (POS.) m/z: 537.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm7.28-8.19 (m, 8 H), 3.90- 4.74 (m, 8 H), 3.46-3.78 (m, 3 H), 2.49-2.62(m, 1 H), 2.00-2.18 (m, 1 H). C (4R)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-4-hydroxy-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 127

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3- (trifluoromethyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 499.1 (M +H)⁺ 1H NMR (400 MHz, Methylene Chloride- d2) δ ppm 8.02 (s, 1 H), 7.96(d, J = 7.8 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.67 (t, J = 7.7 Hz, 1H), 7.58-7.64 (m, 1 H), 7.20 (ddd, J = 3.7, 6.3, 9.4 Hz, 1 H), 5.10-5.16(m, 1 H), 4.53 (t, J = 7.8 Hz, 1 H), 3.30 (dt, J = 3.3, 6.3 Hz, 1 H),2.54-2.61 (m, 1 H), 2.25-2.35 (m, 1 H), 1.30 (s, 1 H), 1.09-1.22 (m, 1H), 0.99-1.06 (m, 1 H), 0.82- 0.89 (m, 1 H), 0.50-0.57 (m, 1 H),0.32-0.39 (m, 1 H). Q 128

(1R,3R,5R)-2-(3-(ethylsulfonyl)benzoyl)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS-APCI(POS.) m/z: 555.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.35 (t,J = 1.7 Hz, 1 H), 8.13 (dt, J = 1.3, 7.7 Hz, 1 H), 8.07 (ddd, J = 1.1,1.9, 7.9 Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.48-7.60 (m, 3 H),5.63-5.69 (m, 1 H), 5.01 (dd, J = 4.2, 11.4 Hz, 1 H), 4.62-4.70 (m, 2H), 4.40 (t, J = 6.3 Hz, 1 H), 3.51-3.62 (m, 1 H), 3.37 (s, 4 H),3.24-3.31 (m, 3 H), 2.62-2.71 (m, 1 H), 1.91 (dd, J = 4.2, 13.5 Hz, 1H), 1.81 (dq, J = 6.2, 9.1 Hz, 1 H), 1.26 (t, J = 7.4 Hz, 4 H),0.85-0.92 (m, 1 H). A 129

(4S)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-(3-(methylsulfonyl)benzoyl)-1,3-thiazolidine-4- carboxamide LCMS-ESI (POS.)m/z: 531.0 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.07-8.18 (m, 2H), 7.79-7.87 (m, 1 H), 7.67- 7.76 (m, 1 H), 7.41-7.50 (m, 2 H), 7.37(d, J = 10.51 Hz, 1 H), 5.03-5.15 (m, 1 H), 4.44- 4.64 (m, 3 H),3.54-3.68 (m, 1 H), 3.27 (dd, J = 11.94, 7.40 Hz, 1 H), 3.02-3.18 (m, 3H), 1.23-1.33 (m, 1 H), 0.60-0.68 (m, 1 H), 0.52-0.60 (m, 1 H),0.36-0.48 (m, 2 H), (1H obscured by CDCl3) C 130

N-(3-chloro-4-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- LCMS-ESI (POS.) m/z:508.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.26 (br t, J = 5.97 Hz,1 H), 7.01-7.36 (m, 3 H), 4.15-4.52 (m, 3 H), 3.99- 4.11 (m, 2 H),3.86-3.99 (m, 2 H), 3.73-3.84 (m, 1 H), 3.62-3.70 (m, 1 H), 3.50-3.61(m, 3 H), 3.35- 3.50 (m, 3 H), 2.71-2.87 (m, 2 H), 2.60-2.70 (m, 1 H),2.04-2.23 (m, 1 H), 1.66-1.97 (m, 5 H), 1.29-1.57 (m, 2 H) A prolinamide131

1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-D- LCMS-APCI (NEG.) m/z: 520.1 (M− H) 1H NMR (400 MHz, Methanol-d4) δ ppm 8.69 (d, J = 2.3 Hz, 1 H), 8.13(q, J = 2.0 Hz, 1 H), 7.95-8.08 (m, 3 H), 7.73- 7.83 (m, 2 H), 4.55-4.71(m, 2 H), 4.49 (d, J = 15.8 Hz, 1 H), 4.08-4.16 (m, 2 H), 3.93 (ddd, J =4.5, 6.2, 8.5 Hz, 2 H), 3.69 (dt, J = 6.8, 10.3 Hz, 1 H), 3.45- 3.64 (m,2 H), 2.32-2.43 (m, 1 H), 1.90-2.07 (m, 3 H). A prolinamide 132

LCMS-ESI (POS.) m/z: 564.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.06- 8.77 (m, 1 H), 7.26-7.41 (m, 4 H), 4.62-4.93 (m, 1 H), 4.28-4.60(m, 1 H), 3.86-4.18 (m, 5 H), 3.34- 3.85 (m, 7 H), 2.58-2.88 (m, 2 H),1.26-2.31 (m, 13 H) A N-(-(4-chlorophenyl)(-tetrahydro-2-furanyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 133

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-(ethylsulfonyl)-2-pyridinyl)carbonyl)-2- LCMS-ESI (POS.) m/z: 524.0 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.41- 9.08 (m, 2 H), 7.93-8.21 (m, 2H), 7.30-7.70 (m, 2 H), 4.85-5.53 (m, 2 H), 4.03-4.61 (m, 2 H), 3.71-3.95 (m, 1 H), 3.34-3.61 (m, 2 H), 2.53-2.84 (m, 1 H), 1.47-1.92 (m, 2H), 0.94-1.30 (m, 4 H), 0.24- 0.84 (m, 4 H), −0.21-0.03 (m, 1 H) Hazabicyclo[3.1.0]hexane-3-carboxamide 134

LCMS-ESI (POS.) m/z: 558.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.12- 8.67 (m, 1 H), 7.66 (br d, J = 7.79 Hz, 2 H), 7.45- 7.59 (m, 2 H),4.79-5.04 (m, 2 H), 4.30-4.59 (m, 1 H), 4.01-4.16 (m, 2 H), 3.89-4.00(m, 2 H), 3.42- 3.84 (m, 7 H), 2.59-2.94 (m, 3 H), 2.01-2.32 (m, 1 H),1.61-2.00 (m, 5 H), 1.27-1.57 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-piperidinyl)carbonyl)-N-(-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide 135

N-((1R)-1-(4-chlorophenyl)ethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- piperidinyl)carbonyl)-D-prolinamideLCMS-ESI (POS.) m/z: 508.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.28-7.31 (m, 2 H), 7.21-7.25 (m, 2 H), 4.96 (quin, J = 7.07 Hz, 1 H),4.54 (br d, J = 6.88 Hz, 1 H), 4.06-4.15 (m, 4 H), 3.77 (br d, J = 12.46Hz, 2 H), 3.52-3.63 (m, 2 H), 3.38-3.47 (m, 1 H), 3.00 (t, J = 11.87 Hz,1 H), 2.67-2.82 (m, 2 H), 2.31-2.43 (m, 1 H), 2.08-2.24 (m, 1 H),1.94-2.06 (m, 2 H), 1.77-1.89 (m, 2 H), 1.56-1.73 (m, 3 H), 1.40 (d, J =6.88 Hz, 3 H) C 136

LCMS-APCI (POS.) m/z: 523.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm8.66-9.02 (m, 2 H), 8.11- 8.27 (m, 1 H), 7.88-8.05 (m, 2 H), 7.60-7.85(m, 1 H), 4.30-4.73 (m, 3 H), 4.06-4.17 (m, 2 H), 3.91-3.99 (m, 2 H),3.47-3.83 (m, 3 H), 2.34-2.47 (m, 1 H), 1.90-2.13 (m, 3 H). A1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-((2-(trifluoromethyl)-5-pyrimidinyl)methyl)-D-prolinamide 137

LCMS-ESI (POS.) m/z: 508.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.26(s, 1 H), 6.98-7.41 (m, 3 H), 4.10-4.52 (m, 3 H), 4.01-4.10 (m, 2 H),3.85-3.99 (m, 2 H), 3.73-3.83 (m, 1 H), 3.41-3.72 (m, 4 H), 2.61-2.90(m, 3 H), 2.26-2.41 (m, 3 H), 2.04-2.28 (m, 1 H), 1.66-1.97 (m, 5 H),1.22-1.60 (m, 2 H) A N-(4-chloro-3-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 138

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-(cyclopropylsulfonyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 536.0 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.77-9.04 (m, 1 H), 8.45-8.66 (m, 1H), 8.12 (dd, J = 14.01, 1.04 Hz, 1 H), 7.92-8.06 (m, 1 H), 7.37-7.67(m, 2 H), 4.84-5.57 (m, 1 H), 3.67- 4.62 (m, 2 H), 2.52-3.21 (m, 2 H),1.48-1.92 (m, 2 H), 1.10-1.30 (m, 4 H), 0.90-1.07 (m, 1 H), −0.25- 0.85(m, 6 H) H 139

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-sulfamoylbenzoyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS-ESI(POS.) m/z: 510.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm8.28-8.35 (m, 1 H), 8.06 (d, J = 7.88 Hz, 1 H), 7.96 (d, J = 7.77 Hz, 1H), 7.63 (t, J = 7.77 Hz, 1 H), 7.49 (br d, J = 7.15 Hz, 1 H), 7.14(ddd, J = 9.30, 5.99, 3.47 Hz, 2 H), 5.34 (br s, 2 H), 5.13 (dd, J =10.31, 3.27 Hz, 1 H), 4.48 (t, J = 7.93 Hz, 1 H), 3.28 (td, J = 6.19,2.64 Hz, 1 H), 2.32-2.50 (m, 2 H), 1.66-1.82 (m, 1 H), 1.11-1.29 (m, 2H), 0.89 (dt, J = 8.73, 6.21 Hz, 1 H), 0.45-0.62 (m, 2 H), 0.26-0.42 (m,2 H) C 140

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-(3-methyl-5-(methylsulfonyl)benzoyl)-2- azabicyc1o[3.1.0]hexane-3-carboxamideLCMS-APCI (POS.) m/z: 539.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.66 (d, J = 8.3 Hz, 1 H), 7.99 (t, J = 1.8 Hz, 1 H), 7.90 (s, 1 H),7.80 (s, 1 H), 7.62-7.71 (m, 1 H), 7.44 (dd, J = 6.3, 9.8 Hz, 1 H),5.34- 5.47 (m, 1 H), 4.87 (dd, J = 3.7, 11.4 Hz, 1 H), 4.63 (dd, J =6.4, 7.7 Hz, 1 H), 4.51 (dd, J = 6.3, 7.8 Hz, 1 H), 4.37 (t, J = 6.1 Hz,1 H), 4.20 (t, J = 6.3 Hz, 1 H), 3.25 (s, 3 H), 2.49 (s, 3 H), 1.64-1.78(m, 2 H), 1.16 (td, J = 2.6, 5.1 Hz, 1 H), 0.77 (dt, J = 5.3, 10.1 Hz, 1H). Q 141

(4S)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-4-fluoro-1-(3- (methylsulfonyl)benzoyl)-D-prolinamideLCMS-APCI (POS.) m/z: 531.1 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.77 (d, J = 8.3 Hz, 1 H), 8.09 (ddd, J = 1.1, 1.9, 7.8 Hz, 1 H),7.86-8.05 (m, 2 H), 7.68-7.83 (m, 1 H), 7.57-7.68 (m, 1 H), 7.47 (dd, J= 6.2, 9.8 Hz, 1 H), 5.48 (t, J = 9.1 Hz, 1 H), 5.20-5.42 (m, 1 H),4.59-5.02 (m, 2 H), 4.38-4.57 (m, 1 H), 4.20-4.37 (m, 1 H), 4.10 (q, J =5.2 Hz, 1 H), 3.87-4.04 (m, 1 H), 3.54- 3.73 (m, 1 H),3.42 (h, J = 6.5Hz, 1 H), 3.28 (s, 2 H), 3.18 (d, J = 5.3 Hz, 1 H), 1.82-2.09 (m, 1 H).A 142

1-((2-((3-cyano-1-azetidinyl)sulfonyl)-4-pyridinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 540.2 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.59-8.95 (m, 1 H), 7.91-8.11(m, 1 H), 7.67 (dd, J = 4.87, 1.45 Hz, 1 H), 7.48-7.56 (m, 1 H), 7.42(d, J = 7.88 Hz, 1 H), 7.31-7.37 (m, 1 H), 7.10 (br t, J = 5.80 Hz, 1H), 4.72 (dd, J = 7.67, 4.66 Hz, 1 H), 4.59 (d, J = 6.01 Hz, 2 H),4.35-4.52 (m, 4 H), 3.38-3.65 (m, 3 H), 2.38- 2.52 (m, 1 H), 2.09-2.26(m, 2 H), 1.88-2.07 (m, 1 H) C 143

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-4,4-difluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 564.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.55 (d, J = 8.30 Hz, 2 H),7.28-7.43 (m, 2 H), 4.74 (br d, J = 6.23 Hz, 1 H), 4.59 (dd, J = 15.70,6.62 Hz, 1 H), 4.38 (dd, J = 15.70, 5.32 Hz, 1 H), 4.05-4.21 (m, 4 H),3.64-3.83 (m, 3 H), 3.40- 3.59 (m, 3 H), 3.12-3.31 (m, 3 H), 2.40-2.59(m, 1 H), 2.22-2.39 (m, 1 H), 2.00-2.20 (m, 3 H), 1.93 (tt, J = 11.74,7.59 Hz, 1 H), 1.68 (br s, 1 H), 1.25-1.43 (m, 3 H) M 144

1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide LCMS-ESI (POS.) m/z: 561.2(M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.29-7.47 (m, 4 H), 5.12-5.30(m, 1 H), 4.53 (dd, J = 1.92, 8.14 Hz, 1 H), 4.08-4.23 (m, 4 H),3.82-3.90 (m, 1 H), 3.79 (dd, J = 3.21, 10.47 Hz, 1 H), 3.69-3.75 (m, 1H), 3.60-3.67 (m, 1 H), 3.42- 3.56 (m, 2 H), 3.14-3.22 (m, 1 H),2.92-3.02 (m, 1 H), 2.74-2.87 (m, 3 H), 2.33-2.41 (m, 1 H), 2.00-2.20(m, 2 H), 1.86-1.99 (m, 1 H), 1.47 (d, J = 6.95 Hz, 3 H) E 145

LCMS-ESI (POS.) m/z: 542.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.16-8.65 (m, 1 H), 7.30-7.63 (m, 3 H), 4.26- 4.54 (m, 3 H), 4.04-4.10(m, 2 H), 3.93 (br d, J = 2.85 Hz, 2 H), 3.73-3.79 (m, 1 H), 3.28-3.63(m, 4 H), 2.71-2.86 (m, 2 H), 2.58-2.71 (m, 1 H), 2.30- 2.39 (m, 3 H),1.66-2.16 (m, 6 H), 1.32-1.56 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methyl-3-(trifluoromethyl)benzyl)-D-prolinamide 146

LCMS-ESI (POS.) m/z: 530.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.29- 8.62 (m, 1 H), 7.40-7.89 (m, 7 H), 4.45-5.04 (m, 2 H), 3.39-3.66(m, 2 H), 2.57-2.71 (m, 6 H), 2.16- 2.32 (m, 1 H), 1.40-1.97 (m, 5 H),0.52-1.03 (m, 3 H) A 1-(3-(dimethylsulfamoyl)benzoyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)propyl)-D- prolinamide 147

LCMS-ESI (POS.) m/z: 531.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.70(d, J = 7.53 Hz, 1 H), 7.63-8.09 (m, 5 H), 7.59 (dd, J = 10.96, 5.38 Hz,1 H), 4.50-4.57 (m, 1 H), 4.11- 4.25 (m, 1 H), 3.40-3.63 (m, 2 H),3.20-3.33 (m,3 H), 2.15-2.32 (m, 1 H), 1.67-1.91 (m, 3 H), 0.90-1.26 (m,1 H), −0.07-0.67 (m, 4 H) A N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 148

LCMS-APCI (POS.) m/z: 554.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.82 (d, J = 7.5 Hz, 1 H), 7.60-7.79 (m, 4 H), 6.69- 6.80 (m, 2 H), 4.97(dd, J = 3.3, 11.7 Hz, 1 H), 4.62 (t, J = 8.0 Hz, 1 H), 3.09 (s, 3 H),2.83 (d, J = 4.9 Hz, 2 H), 1.54-1.78 (m, 3 H), 1.11-1.23 (m, 2 H),0.83-0.91 (m, 1 H), 0.53- 0.69 (m, 2 H), 0.42-0.53 (m, 1 H), 0.36 (d, J= 4.4 Hz, 2 H). S (1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-(methylamino)-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 149

LCMS-ESI (POS.) m/z: 530.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.50(t, J = 5.97 Hz, 1 H), 7.65-7.71 (m, 2 H), 7.44- 7.49 (m, 2 H),4.25-4.40 (m, 3 H), 4.07-4.15 (m, 2 H), 3.91-4.01 (m, 3 H), 3.77-3.89(m, 2 H), 3.56- 3.69 (m, 2 H), 3.36-3.48 (m, 2 H), 2.89-3.08 (m, 2 H),2.05-2.14 (m, 1 H), 1.90-2.00 (m, 1 H), 1.72- 1.87 (m, 2 H) M1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 150

N-((1R)-1-(4-chlorophenyl)ethyl)-1-(((3S)-1-((3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide LCMS-ESI (POS.) m/z: 561.2 (M + H)⁺1H NMR (400 MHz, CHLOROFORM-d) δ 7.25-7.38 (m, 5 H), 4.97 (quin, J =7.13 Hz, 1 H), 4.54 (dd, J = 2.13, 8.03 Hz, 1 H), 4.15-4.29 (m, 4 H),3.90-4.02 (m, 1 H), 3.80 (br d, J = 12.54 Hz, 2 H), 3.48-3.65 (m, 2 H),3.04 (dd, J = 11.04, 12.70 Hz, 1 H), 2.95 (s, 3 H), 2.68-2.89 (m, 2 H),2.32-2.42 (m, 1 H), 2.09- 2.22 (m, 1 H), 1.95-2.09 (m, 2 H), 1.80-1.90(m, 2 H), 1.67-1.72 (m, 1 H), 1.57-1.64 (m, 1 H), 1.41 (d, J = 6.95 Hz,3 H) A 151

N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-(1H-1,2,3-triazol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide LCMS-ESI (POS.) m/z: 588.2 (M + H)⁺1H NMR (400 MHz, CHLOROFORM-d) δ 7.78-7.90 (m, 2 H), 7.29- 7.51 (m, 4H), 5.36-5.52 (m, 1 H), 4.60 (dd, J = 2.07, 8.09 Hz, 1 H), 4.39-4.58 (m,4 H), 4.31 (dd, J = 5.91, 8.91 Hz, 2 H), 3.79-3.88 (m, 2 H), 3.51-3.63(m, 2 H), 2.99-3.14 (m, 1 H), 2.84 (dt, J = 2.80, 12.44 Hz, 1 H), 2.75(tt, J = 3.52, 11.30 Hz, 1 H), 2.44 (tdd, J = 2.85, 6.47, 12.40 Hz, 1H), 2.10-2.23 (m, 1 H), 2.00-2.10 (m, 1 H), 1.79-1.91 (m, 2 H),1.62-1.76 (m, 2 H), 1.50-1.62 (m, 1 H) J 152

LCMS-ESI (POS.) m/z: 508.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.20(s, 1 H), 7.08-7.47 (m, 3 H), 4.16-4.54 (m, 3 H), 3.99-4.13 (m, 2 H),3.86- 3.99 (m, 2 H), 3.73-3.85 (m, 1 H), 3.42-3.69 (m, 4 H), 2.57-2.89(m, 3 H), 2.26- 2.37 (m, 3 H), 2.07-2.16 (m, 1 H), 1.65-1.98 (m, 5 H),1.28-1.57 (m, 2 H) A N-(3-chloro-2-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 153

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,4,5-trifluorobenzyl)-D- prolinamide LCMS-ESI(POS.) m/z: 514.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.67-8.72*(m, 1 H), 8.39 (t, J = 6.10 Hz, 1 H), 7.14-7.21 (m, 2 H), 4.17- 4.35 (m,3 H), 3.99-4.09 (m, 2 H), 3.89-3.98 (m, 2 H), 3.75-3.82 (m, 1 H),3.30-3.71 (m, 4 H), 2.70- 2.86 (m, 2 H), 2.64-2.69 (m, 1 H), 2.27-2.35*(m, 1 H), 2.18-2.27* (m, 1 H), 2.04- 2.17 (m, 1 H), 1.67-1.97 (m, 5 H),1.35-1.56 (m, 2 H). Spectrum appears as 3:1 mixture of rotamers,*denotes resolved minor rotamer peaks. 154

LCMS-APCI (POS.) m/z: 572.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.89 (d, J = 7.6 Hz, 1 H), 7.69 (ddd, J = 8.4, 18.2, 20.8 Hz, 3 H), 7.57(s, 1 H), 6.85 (d, J = 9.0 Hz, 1 H), 6.68 (t, 1 H), 4.54-4.81 (m, 3 H),4.35 (t, J = 5.1 Hz, 1 H), 3.57 (q, J = 5.3 Hz, 2 H), 3.21-3.36 (m, 9H), 3.11 (s, 2 H), 2.14-2.30 (m, 2 H), 1.60-1.82 (m, 3 H), 1.13-1.28 (m,1 H), 0.54-0.65 (m, 1 H), 0.46- 0.54 (m, 1 H), 0.39 (s, 2 H). SN-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(2-((2-hydroxyethyl)amino)-5-(methylsulfonyl)benzoyl)- D-prolinamide 155

LCMS-ESI (POS.) m/z: 506.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.06-8.62 (m, 1 H), 7.14-7.29 (m, 1 H), 6.93-7.13 (m, 2 H), 4.74- 4.99(m, 1 H), 4.23-4.48 (m, 1 H), 3.73-4.12 (m, 5 H), 3.47-3.66 (m, 4 H),2.63-2.89 (m, 3 H), 2.12- 2.35 (m, 4 H), 1.61-2.11 (m, 6 H), 1.31-1.57(m, 4 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(-1-(3-fluoro-4-methylphenyl)ethyl)-D-prolinamide, 156

1-(((3S)-1-((3-cyano-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 542.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (d, J = 8.04 Hz, 2 H),7.38-7.46 (m, 1 H), 7.35 (d, J = 7.78 Hz, 2 H), 4.60 (dd, J = 8.04, 1.82Hz, 1 H), 4.49-4.55 (m, 1 H), 4.37-4.46 (m, 1 H), 4.18 (d, J = 8.04 Hz,2 H), 3.73-3.81 (m, 4 H), 2.95 (dd, J = 12.72, 10.90 Hz, 1 H), 2.63-2.82(m, 2 H), 2.41-2.51 (m, 1 H), 2.12-2.25 (m, 1 H), 2.01-2.11 (m, 1 H),1.58-1.96 (m, 8 H), 1.45-1.56 (m, 1 H), 1.21-1.35 (m, 2 H) M 157

LCMS-ESI (POS.) m/z: 485.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.57(t, J = 5.97 Hz, 1 H), 7.62-8.06 (m, 4 H), 6.94- 7.44 (m, 4 H),5.38-5.47 (m, 1 H), 5.29-5.35 (m, 1 H), 3.78-4.55 (m, 8 H), 3.60-3.67(m, 2 H), 2.17- 2.31 (m, 1 H), 1.76-1.97 (m, 3 H) F 1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(fluoromethyl)benzyl)-D-prolinamide 158

LCMS-ESI (POS.) m/z: 551.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.30-8.60 (m, 1 H), 7.44-8.04 (m, 8 H), 4.66- 5.05 (m, 2 H), 4.32-4.60(m, 1 H), 3.83-4.08 (m, 4 H), 3.34-3.72 (m, 5 H), 2.21-2.32 (m, 1 H),1.72- 1.90 (m, 3 H) A 1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1S)-2-hydroxy-1-(3- (trifluoromethyl)phenyl)ethyl)-D-prolinamide 159

(2R)-N-((R)-(4-chloro-2,5- difluorophenyl)(cyclopropyl)methyl)-1-((4-LCMS-ESI (POS.) m/z: 512.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.79-9.01 (m, 1 H), 8.44-8.70 (m, 1 H), 7.95-8.09 (m, 2 H), 7.45- 7.67(m, 2 H), 4.42-5.20 (m, 2 H), 3.39 (d, J = 13.23 Hz, 4 H), 3.00-3.13 (m,1 H), 2.16 (br s, 1 H), 1.11-1.75 (m, 6 H), 0.29- 0.62 (m, 4 H) C(methylsulfonyl)-2-pyridinyl)carbonyl)-2- piperidinecarboxamide 160

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(ethylsulfonyl)-3-pyridinyl)carbonyl)-2- LCMS-ESI (POS.) m/z: 524.0 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.85- 9.20 (m, 2 H), 8.19-8.73 (m, 2H), 7.55-7.69 (m, 1 H), 7.30-7.53 (m, 1 H), 4.62-5.00 (m, 1 H), 3.97-4.56 (m, 1 H), 3.28-3.79 (m, 3 H), 2.54-2.81 (m, 1 H), 1.54-1.88 (m, 2H), 1.04- 1.26 (m, 5 H), 0.40-0.85 (m, 3 H), −0.31-0.39 (m, 3 H) Hazabicyclo[3.1.0]hexane-3-carboxamide 161

LCMS-ESI (POS.) m/z: 539.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.54(d, J = 7.79 Hz, 1 H) 7.35- 8.24 (m, 7 H) 4.62-5.11 (m, 2 H) 3.21-3.28(m, 4 H) 2.52- 2.59 (m, 1 H) 1.13-2.35(m, 9 H) 0.62-1.13 (m, 2 H) A(1R,3R,5R)-N-((R)-cyclobutyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3- (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 162

N-(4-chlorobenzyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-methyl- prolinamide LCMS-APCI(POS.) m/z: 501.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.13 (t,J = 2.1 Hz, 1 H), 8.00 (dt, J = 1.6, 7.4 Hz, 2 H), 7.81 (td, J = 1.3,7.9 Hz, 1 H), 7.49 (d, J = 8.5 Hz, 1 H), 7.38-7.42 (m, 1 H), 7.32 (dd, J= 2.2, 8.2 Hz, 2 H), 5.08 (dt, J = 5.6, 8.2 Hz, 1 H), 4.42 (d, J = 15.2Hz, 1 H), 4.00-4.22 (m, 3 H), 3.91-3.97 (m, 2 H), 3.70 (dq, J = 6.1,6.7, 13.5 Hz, 1 H), 3.55-3.62 (m, 1 H), 3.52 (ddt, J = 2.4, 6.2, 12.4Hz, 1 H), 3.04 (s, 3 H), 2.39-2.54 (m, 1 H), 2.02-2.12 (m, 1 H), 1.89-2.02 (m, 2 H). A 163

LCMS-ESI (POS.) m/z: 536.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.84- 9.29 (m, 2 H), 8.17-8.75 (m, 2 H), 7.25-7.72 (m, 2 H), 4.65-5.02(m, 1 H), 4.01- 4.58 (m, 1 H), 3.28-3.86 (m, 1 H), 2.96-3.20 (m, 1 H),2.54-2.83 (m, 1 H), 1.52- 1.85 (m, 2 H), 1.04-1.33 (m, 6 H), −0.32-0.98(m, 6 H) H (1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(cyclopropylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 164

N-(4-chlorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide LCMS-ESI(POS.) m/z: 494.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.67* (t, J =5.84 Hz, 1 H), 8.31 (t, J = 6.03 Hz, 1 H), 7.34- 7.41 (m, 2 H),7.23-7.29 (m, 2 H), 4.19-4.50 (m, 3 H), 4.01-4.10 (m, 2 H), 3.90- 3.98(m, 2 H), 3.75-3.83 (m, 1 H), 3.30-3.68 (m, 4 H), 2.72-2.86 (m, 2 H),2.64 (tdd, J = 11.09, 11.09, 3.44, 3.31 Hz, 1 H), 2.25-2.33* (m, 1 H),2.16-2.25* (m, 1 H), 2.04-2.13 (m, 1 H), 1.67-1.98 (m, 5 H), 1.35-1.54(m, 2 H). Spectrum appears as 2:1 mixture of rotamers, *denotes resolvedminor rotamer peaks. C 165

LCMS-ESI (POS.) m/z: 517.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.17- 8.48 (m, 1 H), 6.63-8.02 (m, 7 H), 4.50-4.74 (m, 2 H), 3.75-4.09(m, 4 H), 3.44-3.70 (m, 3 H), 2.21- 2.38 (m, 1 H), 1.46-2.05 (m, 5 H),0.67-0.97 (m, 3 H) A 1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1S)-1-(3,5-difluorophenyl)propyl)-D-prolinamide 166

LCMS-ESI (NEG.) m/z: 595.2 (M − H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.24-8.75 (m, 1 H), 7.60-7.74 (m, 2 H), 7.06-7.51 (m, 6 H), 5.06-5.21(m, 1 H), 4.21- 4.47 (m, 3 H), 3.79-3.95 (m, 1 H), 3.35-3.73 (m, 6 H),2.57-2.73 (m, 2 H), 2.02-2.39 (m, 3 H), 1.51-2.02 (m, 5 H), 1.11-1.41(m, 2 H) J 1-(((3S)-1-((-2-(3-fluorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 167

LCMS-ESI (POS.) m/z: 543.0 (M + Na)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δppm 7.89-8.01 (m, 2 H), 7.58-7.84 (m, 4 H), 7.40- 7.52 (m, 2 H),6.81-6.97 (m, 1 H), 5.08-5.24 (m, 2 H), 4.12-4.22 (m, 2 H), 3.99-4.10(m, 2 H), 3.34-3.44 (m, 1 H), 2.88-3.19 (m, 3 H), 1.46-1.56 (m, 6 H) C3-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-(((1S)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)benzamide 168

1-((1-((3-cyano-1-azetidinyl)sulfonyl)-4-fluoro-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 544.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.58 (m, J = 8.04 Hz, 2 H),7.28-7.45 (m, 2 H), 7.16-7.26 (m, 1 H), 4.67 (dd, J = 7.66, 4.02 Hz, 1H), 4.51-4.61 (m, 1 H), 4.29-4.51 (m, 1 H), 4.02- 4.18 (m, 5 H),3.83-4.01 (m, 1 H), 3.55-3.64 (m, 3 H), 3.38-3.53 (m, 2 H), 2.51- 2.62(m, 1 H), 2.40-2.51 (m, 2 H), 2.01-2.20 (m, 2 H), 1.88-2.01 (m, 1 H) M169

N-((1S)-1-(4-chlorophenyl)-2-hydroxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide LCMS-ESI (POS.) m/z: 524.2 (M + H)⁺1H NMR (500 MHz, DMSO-d6) δ ppm 8.12 (d, J = 8.04 Hz, 1 H), 7.19-7.45(m, 4 H), 4.77 -4.87 (m, 1 H), 4.49-4.54 (m, 1 H), 4.33 (br d, J = 4.41Hz, 1 H), 3.98-4.11 (m, 2 H), 3.89-3.95 (m, 1 H), 3.96 (s, 1 H), 3.70-3.84 (m, 1 H), 3.27-3.61 (m, 6 H), 2.70-2.90 (m, 2 H), 2.60-2.66 (m, 1H), 2.00-2.22 (m, 1 H), 1.59- 1.91 (m, 5 H), 1.30-1.56 (m, 2 H) A 170

LCMS-ESI (POS.) m/z: 565.2 (M + Na)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δppm 7.58 (t, J = 8.19 Hz, 2 H), 7.28-7.45 (m, 3 H), 4.38-4.65 (m, 3 H),4.00-4.19 (m, 4 H), 3.00-3.78 (m, 8 H), 2.85 (br dd, J = 9.12, 4.56 Hz,1 H), 2.31-2.52 (m, 1 H), 2.10-2.28 (m, 2 H), 1.56-2.08 (m, 4 H), 1.05(d, J = 7.26 Hz, 1 H), 0.75-0.87 (m, 1 H) M1-((-1-((3-cyano-1-azetidinyl)sulfonyl)-4-methyl-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 171

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyc1o[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 516.1 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.94 (d, J = 5.1 Hz, 1 H), 8.69 (d,J = 8.1 Hz, 1 H), 7.88-8.02 (m, 1 H), 7.61- 7.73 (m, 1 H), 7.44 (dd, J =6.3, 9.7 Hz, 1 H), 5.41 (t, J = 9.0 Hz, 1 H), 4.87 (dd, J = 3.6, 11.3Hz, 1 H), 4.63 (dd, J = 6.3, 7.7 Hz, 1 H), 4.46-4.54 (m, 1 H), 4.37 (t,J = 6.2 Hz, 1 H), 4.16-4.26 (m, 1 H), 3.36-3.47 (m, 1 H), 1.67- 1.78 (m,1 H), 1.08-1.19 (m, 1 H), 0.66-0.81 (m, 1 H). Q 172

1-(((1R,4R,6R)-2-((3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[2.2.1]hept-6-yl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 540.2 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.50-7.65 (m, 2 H), 7.31-7.44 (m, 3H), 4.56 (dd, J = 2.33, 8.03 Hz, 1 H), 4.46-4.53 (m, 1 H), 4.38-4.45 (m,1 H), 4.01- 4.19 (m, 5 H), 3.54-3.70 (m, 2 H), 3.41 (tt, J = 6.32, 8.76Hz, 1 H), 3.21-3.30 (m, 1 H), 3.11 (dd, J = 5.29, 8.50 Hz, 1 H), 3.06(d, J = 8.81 Hz, 1 H), 2.65 (br s, 1 H), 2.41 (tdd, J = 3.01, 6.44,12.32 Hz, 1 H), 2.14- 2.23 (m, 1 H), 2.00-2.09 (m, 1 H), 1.86-1.98 (m, 2H), 1.76-1.86 (m, 2 H), 1.58- 1.69 (m, 1 H) M 173

(4S)-N-((R)-cyclopropyl(2,5-difluoro-4- LCMS-ESI (POS.) m/z: 549.0 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.88 (d, J = 7.27 Hz, 1 H),7.66-8.15 (m, 5 H), 7.38- 7.62 (m, 1 H), 5.19-5.42 (m, 1 H), 4.52-4.73(m, 2 H), 3.83-3.99 (m, 1 H), 3.49-3.67 (m, 1 H), 3.23- 3.34 (m, 3 H),2.52-2.59 (m, 1 H), 1.83-2.07 (m, 1 H), 0.84-1.32 (m, 1 H), −0.25- 0.63(m, 4 H) C (trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 174

N-(4-chloro-3-fluorobenzyl)-1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-D- LCMS-ESI (POS.) m/z:513.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.30-7.45 (m, 2 H),6.93-7.14 (m, 2 H), 4.53- 4.73 (m, 1 H), 4.26-4.50 (m, 2 H), 4.06-4.25(m, 4 H), 3.80-3.90 (m, 1 H), 3.68-3.80 (m, 2 H), 3.59- 3.68 (m, 1 H),3.41-3.59 (m, 2 H), 3.15 (br d, J = 13.37 Hz, 1 H), 2.80-3.00 (m, 4 H),2.37-2.51 (m, 1 H), 1.90-2.23 (m, 3 H) E prolinamide 175

LCMS-ESI (POS.) m/z: 558.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.41-8.63 (m, 1 H), 7.68 (br d, J = 8.17 Hz, 2 H), 7.44-7.58 (m, 3 H),4.92-5.10 (m, 1 H), 4.49- 4.77 (m, 1 H), 4.44 (br d, J = 11.81 Hz, 1 H),4.23- 4.48 (m, 1 H), 3.89-4.14 (m, 5 H), 3.27-3.84 (m, 5 H), 2.71-2.97(m, 3 H), 1.76-1.92 (m, 1 H), 1.63- 1.76 (m, 1 H), 1.22-1.58 (m, 5 H) B(3R)-4-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4- (trifluoromethyl)phenyl)ethyl)-3-morpholinecarboxamide 176

LCMS-ESI (POS.) m/z: 524.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.05-8.50 (m, 1 H), 6.87-7.21 (m, 3 H), 4.29-4.51 (m, 1 H), 4.11-4.27(m, 2 H), 3.72-4.12 (m, 8 H), 3.43-3.70 (m, 4 H), 2.59-2.91 (m, 3 H),1.69-2.34 (m, 6 H), 1.32-1.58 (m, 2 H) AN-(4-chloro-2-methoxybenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- piperidinyl)carbonyl)-D-prolinamide 177

LCMS-ESI (POS.) m/z: 540.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.38-7.74 (m, 1 H), 5.96-6.20 (m, 1 H), 5.92- 6.47 (m, 1 H), 4.40-4.69(m, 3 H), 4.01-4.16 (m, 4 H), 3.60-3.92 (m, 4 H), 3.39- 3.49 (m, 1 H),3.02 (s, 3 H), 1.57-2.02 (m, 6 H), 0.77- 1.00 (m, 2 H) C(1S,2R,5R)-3-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-3- azabicyclo[3.1.0]hexane-2-carboxamide 178

LCMS-ESI (POS.) m/z: 539.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.33- 8.74 (m, 1 H), 7.03-8.19 (m, 6 H), 4.94 (dd, J = 11.42, 3.63 Hz, 2H), 4.53 (br t, J = 7.91 Hz, 1 H), 3.18-3.44 (m, 2 H), 2.56 (td, J =12.59, 6.23 Hz, 1 H), 1.51-1.80 (m, 2 H), 1.03- 1.26 (m, 4 H),−0.27-0.95 (m, 5 H) C (1R,3R,5R)-N-((R)-cyclopropyl(4-(difluoromethyl)-2,5-difluorophenyl)methyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane- 3-carboxamide 179

N-((R)-(3-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)- D-prolinamide LCMS-APCI(POS.) m/z: 529.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.23 (t,J = 1.7 Hz, 1 H), 8.05-8.13 (m, 2 H), 7.96 (dt, J = 1.4, 7.7 Hz, 1 H),7.63-7.81 (m, 3 H), 7.31-7.38 (m, 2 H), 7.20 (dd, J = 5.2, 9.2 Hz, 1 H),5.45-5.52 (m, 1 H), 4.88 (d, J = 14.2 Hz, 5 H), 4.64-4.72 (m, 2 H),4.55-4.62 (m, 1 H), 4.44-4.54 (m, 2 H), 3.71-3.78 (m, 1 H), 3.66 (dt, J= 7.2, 10.2 Hz, 1 H), 3.53 (dddd, J = 5.4, 7.0, 10.2, 13.7 Hz, 2 H),3.37 (s, 1 H), 3.19 (s, 4 H), 2.36 (tdd, J = 5.6, 8.9, 11.8 Hz, 1 H),1.96-2.06 (m, 1 H), 1.81-1.96 (m, 3 H). A 180

LCMS-ESI (POS.) m/z: 657.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ 8.26-8.76 (m, 1 H), 7.58-7.83 (m, 3 H), 7.24-7.58 (m, 5 H), 5.05-5.19 (m, 1H), 4.23-4.47 (m, 3 H), 3.80- 3.96 (m, 1 H), 3.42-3.78 (m, 6 H),2.60-2.75 (m, 2 H), 2.01-2.37 (m, 3 H), 1.55-2.01 (m, 5 H), 1.10- 1.45(m, 2H) J 1-(((3S)-1-((-2-(3-bromophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide, 181

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4- methylbenzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 492.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.09-7.24 (m, 2 H), 6.80-6.96 (m, 2 H), 4.50- 4.60 (m, 1 H), 4.35-4.47(m, 2 H), 4.04-4.16 (m, 4 H), 3.69-3.79 (m, 2 H), 3.52-3.63 (m, 2 H),3.37- 3.47 (m, 1 H), 2.91-3.03 (m, 1 H), 2.64-2.82 (m, 2 H), 2.27-2.40(m, 4 H), 2.10-2.24 (m, 1 H), 1.97-2.08 (m, 1 H), 1.86-1.97 (m, 2 H),1.75-1.83 (m, 1 H), 1.49-1.71 (m, 2 H) A 182

(1R,3R,5R)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2- LCMS-APCI (POS.) m/z: 541.1 (M + H)⁺ 1H NMR(400 MHz, Methanol-d4) δ ppm 8.39 (t, J = 1.7 Hz, 1 H), 8.10-8.15 (m, 2H), 7.79 (t, J = 7.8 Hz, 1 H), 7.48- 7.58 (m, 3 H), 5.66 (d, J = 10.2Hz, 1 H), 5.01 (dd, J = 4.2, 11.4 Hz, 1 H), 4.61- 4.70 (m, 2 H),4.37-4.42 (m, 1 H), 3.52-3.62 (m, 1 H), 3.19 (s, 3 H), 2.67 (dddd, J =1.1, 6.5, 11.5, 13.3 Hz, 1 H), 1.91 (dd, J = 4.2, 13.6 Hz, 1 H),1.77-1.84 (m, 1 H), 1.25 (td, J = 2.7, 5.3 Hz, 1 H), 0.90 (dtd, J = 1.1,5.7, 9.0 Hz, 1 H). A azabicyclo[3.1.0]hexane-3-carboxamide 183

LCMS-ESI (POS.) m/z: 546.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.46- 8.56 (m, 1 H), 7.68 (d, J = 8.17 Hz, 2 H), 7.44-7.48 (m, 2 H),4.29-4.74 (m, 3 H), 4.02-4.09 (m, 2 H), 3.88-3.98 (m, 2 H), 3.68-3.88(m, 3 H), 3.33-3.63 (m, 3 H), 2.90-2.99 (m, 1 H), 2.03-2.23 (m, 2 H),1.59-2.01 (m, 6 H) M 1-((-1-((3-cyano-1-azetidinyl)sulfonyl)-3-fluoro-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 184

(1R,3R,5R)-2-(3-(1- carbamoylcyclopropyl)benzoyl)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 530.2 (M +H)⁺ 1H NMR (Methanol-d4) δ: 7.88-7.81 (m, 1 H), 7.72 (d, J = 7.6, 1.5Hz, 1 H), 7.59 (d, J = 7.7, 1.5 Hz, 1 H), 7.51 (t, J = 7.7 Hz, 1 H),7.39 (dd, J = 9.4, 6.1 Hz, 1 H), 7.28 (dd, J = 9.4, 6.3 Hz, 1 H), 5.57(d, J = 10.2 Hz, 1 H), 4.98 (dd, J = 11.4, 4.2 Hz, 1 H), 4.83 (t, J =7.6, 6.5 Hz, 1 H), 4.67 (t, J = 7.8, 6.4 Hz, 1 H), 4.60 (t, J = 6.2 Hz,1 H), 4.38 (t, J = 6.2 Hz, 1 H), 3.59-3.45 (m, 1 H), 3.42-3.35 (m, 1 H),3.35-3.30 (m, 2 H), 2.73-2.55 (m, 1 H), 1.91 (dd, J = 13.5, 4.2 Hz, 1H), 1.83-1.73 (m, 1 H), 1.61-1.48 (m, 2 H), 1.29-1.21 (m, 1 H),1.21-1.09 (m, 2 H), 0.90-0.82 (m, 1 H) V 185

LCMS-ESI (POS.) m/z: 544.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.26-8.56 (m, 1 H), 7.40-7.91 (m, 7 H), 4.45-4.93 (m, 2 H), 3.41-3.63(m, 2 H), 2.53-2.75 (m, 6 H), 2.12-2.36 (m, 1 H), 1.59-2.06 (m, 4 H),0.47-1.07 (m, 6 H) A 1-(3-(dimethylsulfamoyl)benzoyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)- D-prolinamide 186

N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-((2-methyl-2- LCMS-APCI (POS.) m/z:584.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 7.73 (dd, 1 H), 7.69(d, J = 2.4 Hz, 1 H), 7.66 (d, J = 7.5 Hz, 1 H), 7.48 (dd, J = 9.5, 29.4Hz, 2 H), 7.11 (d, J = 9.0 Hz, 1 H), 4.64- 4.69 (m, 1 H), 4.59 (d, J =9.1 Hz, 2 H), 3.45-3.54 (m, 1 H), 3.39-3.46 (m, 1 H), 3.07 (s, 3 H),2.33-2.43 (m, 1 H), 1.84-1.95 (m, 3 H), 1.43 (s, 8 H), 1.31 (s, 3 H),0.85-0.96 (m, 1 H), 0.67- 0.75 (m, 1 H), 0.50-0.62 (m, 2 H), 0.41-0.49(m, 1 H). S propanyl)amino)-5-(methylsulfonyl)benzoyl)-D- prolinamide187

N-(4-chloro-2-fluorobenzyl)-1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-D- prolinamide LCMS-ESI(POS.) m/z: 514.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.22-7.27(m, 1 H), 7.05-7.17 (m, 3 H), 4.56- 4.78 (m, 1 H), 4.37-4.52 (m, 2 H),4.12-4.22 (m, 5 H), 3.91-4.02 (m, 1 H), 3.81 (ddd, J = 4.04, 8.09, 10.47Hz, 1 H), 3.61-3.74 (m, 2 H), 3.42-3.56 (m, 3 H), 3.19 (dd, J = 9.48,12.70 Hz, 1 H), 3.05 (ddd, J = 3.27, 10.70, 12.47 Hz, 1 H), 2.35- 2.43(m, 1 H), 2.08-2.20 (m, 1 H), 1.86-2.04 (m, 2 H) C 188

LCMS-ESI (POS.) m/z: 551.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.48(d, J = 7.92 Hz, 1 H), 7.18-8.03 (m, 8 H), 4.87- 4.96 (m, 1 H), 4.60 (brdd, J = 7.91, 5.06 Hz, 1 H), 3.78-4.03 (m, 4 H), 3.41- 3.70 (m, 5 H),3.38-4.07 (m, 1 H), 2.19-2.34 (m, 1 H), 1.70-2.02 (m, 3 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N- ((1R)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D- prolinamide 189

LCMS-ESI (POS.) m/z: 558.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ7.41-7.54 (m, 2 H), 7.34-7.41 (m, 2 H), 7.28-7.34 (m, 1 H), 4.40-4.61(m, 3 H), 4.02-4.19 (m, 5 H), 3.48-3.82 (m, 2 H), 3.35-3.47 (m, 1 H),3.22- 3.30 (m, 1 H), 3.04-3.19 (m, 2 H), 2.62-2.72 (m, 1 H), 2.35-2.48(m, 1 H), 2.13-2.24 (m, 1 H), 1.97- 2.09 (m, 1 H), 1.74-1.97 (m, 3 H),1.63-1.73 (m, 1 H) M 1-((2-((3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[2.2.1]hept-6-yl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide 190

N-(3-chlorobenzyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D- prolinamide LCMS-APCI (NEG.)m/z: 485.1 (M − H) 1H NMR (400 MHz, MeOD) δ ppm 8.14 (d, J = 1.7 Hz, 1H), 7.94-8.04 (m, 2 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.36 (t, J = 2.0 Hz,1 H), 7.19- 7.34 (m, 3 H), 4.60 (dd, J = 5.9, 8.1 Hz, 1 H), 4.44 (q, J =15.4 Hz, 2 H), 4.11 (td, J = 1.1, 8.7 Hz, 2 H), 3.93 (ddd, J = 4.8, 6.2,8.5 Hz, 2 H), 3.54 (dddd, J = 5.3, 7.7, 15.0, 17.7 Hz, 2 H), 2.32-2.41(m, 1 H), 1.99- 2.06 (m, 2 H), 1.86-1.96 (m, 1 H). A 191

N-(2-chloro-4-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide LCMS-ESI(POS.) m/z: 508.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.25 (s, 1H), 7.05-7.31 (m, 3 H), 4.16-4.53 (m, 3 H), 4.01-4.10 (m, 2 H),3.89-3.99 (m, 2 H), 3.73- 3.82 (m, 1 H), 3.42-3.72 (m, 4 H), 3.31-3.38(m, 3 H), 2.71-2.89 (m, 2 H), 2.61-2.70 (m, 1 H), 2.48- 2.52 (m, 5 H),2.02-2.24 (m, 1 H), 1.62-2.00 (m, 5 H), 1.31-1.60 (m, 2 H) A 192

1-(((3S)-1-(((3S)-3-cyano-1-pyrrolidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 542.2 (M + Na)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δppm 7.57 (br d, J = 7.88 Hz, 2 H), 7.31-7.45 (m, 3 H), 4.34-4.66 (m, 3H), 3.80 (br d, J = 12.44 Hz, 2 H), 3.56-3.70 (m, 3 H), 3.42-3.56 (m, 3H), 3.17 (quin, J = 6.38 Hz, 1 H), 2.93-3.10 (m, 1 H), 2.69-2.93 (m, 2H), 2.14- 2.43 (m, 4 H), 1.45-2.12 (m, 6 H) M 193

(1R,3R,5R)-N-((R)-(3-fluoro-4- (trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo‘3.1.0’hexane-3-carboxamide LCMS-APCI (POS.) m/z: 541.1 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.39 (t, 1 H), 8.09-8.15 (m, 2H), 7.79 (t, 1 H), 7.71 (t, 1 H), 7.29-7.35 (m, 2 H), 5.40 (d, J = 10.1Hz, 1 H), 5.02 (dd, J = 4.3, 11.4 Hz, 1 H), 4.84 (dd, J = 6.5, 7.7 Hz, 1H), 4.67 (dd, J = 6.4, 7.9 Hz, 1 H), 4.61 (t, J = 6.3 Hz, 1 H), 4.46 (t,J = 6.3 Hz, 1 H), 3.50 (dtt, J = 6.1, 7.8, 10.2 Hz, 1 H), 3.37 (s, 2 H),3.19 (s, 3 H), 2.69 (dddd, J = 1.1, 6.5, 11.4, 13.5 Hz, 1 H), 1.93 (dd,1 H), 1.78-1.86 (m, 1 H), 1.28 (td, J = 2.7, 5.3 Hz, 1 H), 0.91 (dtd, J= 1.0, 5.7, 8.9 Hz, 1 H). A 194

(2R)-N-((R)-(4-chloro-2,5- difluorophenyl)(cyclopropyl)methyl)-1-(3-sulfamoylbenzoyl)-2-piperidinecarboxamide LCMS-ESI (NEG.) m/z: 510.0 (M− H)⁻ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.05-8.16 (m, 1 H), 7.92-8.04(m, 1 H), 7.66-7.78 (m, 1 H), 7.59 (t, J = 7.77 Hz, 1 H), 7.40- 7.48 (m,1 H), 7.04- 7.20 (m, 2 H), 5.32- 5.84 (m, 2 H), 4.72 (t, J = 6.84 Hz, 1H), 4.48 (dd, J = 8.55, 7.20 Hz, 1 H), 3.57-3.88 (m, 1 H), 3.40-3.54 (m,1 H), 1.94- 2.28 (m, 3 H), 1.80-1.93 (m, 1 H), 1.06 (br d, J = 3.11 Hz,1 H), 0.48-0.65 (m, 2 H), 0.17-0.47 (m, 2 H) C 195

LCMS-ESI (POS.) m/z: 556.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.15(d, J = 8.30 Hz, 1 H), 7.50-7.75 (m, 4 H), 4.68-4.84 (m, 1 H), 4.29-4.48 (m, 1 H), 3.88-4.10 (m, 4 H), 3.74-3.83 (m, 1 H), 3.28-3.48 (m, 2H), 2.68-2.88 (m, 2 H), 2.58- 2.66 (m, 1 H), 1.18-2.26 (m, 12 H),0.79-0.91 (m, 3 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide 196

1-(((3S)-1-((3-ethynyl-3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z:561.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.29-7.47 (m, 4 H),4.56-4.63 (m, 1 H), 4.42 -4.56 (m, 2 H), 4.09-4.15 (m, 2 H), 4.02 (dd, J= 3.63, 8.29 Hz, 2 H), 3.73- 3.85 (m, 2 H), 3.53-3.65 (m, 2 H),2.93-3.05 (m, 2 H), 2.76-2.86 (m, 1 H), 2.71-2.76 (m, 1 H), 2.37- 2.47(m, 1 H), 2.09-2.24 (m, 1 H), 1.99-2.09 (m, 1 H), 1.77-1.96 (m, 3 H),1.53-1.72 (m, 3 H) J 197

LCMS-ESI (POS.) m/z: 525.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.34- 8.73 (m, 1 H), 7.62-8.22 (m, 4 H), 6.99-7.58 (m, 2 H), 6.98-7.37(m, 1 H), 4.03-5.05 (m, 3 H), 1.50- 1.81 (m, 2 H), 1.02-1.25 (m, 2 H),−0.27-0.97 (m, 5 H) C (1R,3R,5R)-N-((R)-cyclopropyl(4-(difluoromethyl)-2,5-difluorophenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide 198

LCMS-ESI (POS.) m/z: 596.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 9.22(d, J = 9.34 Hz, 1 H), 7.64-7.94 (m, 4 H), 5.89 (s, 1 H), 4.44 (dd, J =8.56, 4.15 Hz, 1 H), 4.01- 4.14 (m, 2 H), 3.89-4.01 (m, 2 H), 3.74-3.85(m, 1 H), 3.27-3.64 (m, 4 H), 2.72-2.91 (m, 2 H), 2.56- 2.69 (m, 1 H),2.01-2.22 (m, 1 H), 1.30-1.92 (m, 7 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide 199

1-(((3S)-1((3-cyclopropyl-3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z:577.1 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.40-7.51 (m, 2 H),7.34-7.40 (m, 1 H), 7.29- 7.34 (m, 1 H), 4.59 (dd, J = 2.18, 7.98 Hz, 1H), 4.43-4.57 (m, 2 H), 3.73- 3.83 (m, 4 H), 3.51-3.69 (m, 4 H), 2.96(dd, J = 10.88, 12.65 Hz, 1 H), 2.67-2.82 (m, 2 H), 2.37-2.46 (m, 1 H),2.09-2.23 (m, 1 H), 1.98-2.09 (m, 1 H), 1.76-1.95 (m, 3 H), 1.50-1.72(m, 3 H), 1.24 (tt, J = 5.21, 8.32 Hz, 1 H), 0.53-0.64 (m, 2 H), 0.42-0.49 (m, 2 H) J 200

1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 547.2 (M +Na)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42-7.50 (m, 1 H), 7.34-7.42(m, 2 H), 7.31 (d, J = 9.95 Hz, 1 H), 4.43-4.62 (m, 3 H), 4.09- 4.19 (m,4 H), 3.76-3.95 (m, 1 H), 3.66-3.73 (m, 2 H), 3.41-3.63 (m, 3 H), 3.14(br d, J = 13.68 Hz, 1 H), 2.74-2.97 (m, 3 H), 2.36- 2.53 (m, 1 H),2.01-2.20 (m, 2 H), 1.78-1.99 (m, 2 H) M 201

LCMS-ESI (POS.) m/z: 515.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.46-8.85 (m, 1 H), 7.26-8.13 (m, 6 H), 5.21- 5.45 (m, 1 H), 3.88-4.76(m, 3 H), 3.58-3.68 (m, 2 H), 3.26-3.30 (m, 3 H), 1.82-2.05 (m, 1 H),0.80- 1.32 (m, 1 H), −0.28-0.63 (m, 4 H) C (4S)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 202

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-(methylsulfonyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 510.0 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.78-9.05 (m, 1 H), 8.42-8.67 (m, 1H), 8.13-8.26 (m, 1 H), 7.99- 8.08 (m, 1 H), 7.53-7.70 (m, 1 H),7.36-7.53 (m, 1 H), 4.86-5.51 (m, 1 H), 4.11-4.56 (m, 1 H), 3.84- 3.97(m, 1 H), 3.39 (d, J = 8.82 Hz, 3 H), 2.54-2.79 (m, 1 H), 1.70-1.90 (m,1 H), 1.53-1.68 (m, 1 H), 0.45-1.22 (m, 4 H), 0.25- 0.37 (m, 2 H),−0.20-0.02 (m, 1 H) C 203

LCMS-ESI (POS.) m/z: 570.2 (M + Na)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.38- 8.82 (m, 7 H), 5.54 (br d, J = 7.78 Hz, 1 H), 4.13- 4.46 (m, 7 H),3.49-3.81 (m, 4 H), 2.59-2.97 (m, 3 H), 1.34-2.26 (m, 8 H) M1-(((3S)-1-((3-(1H-1,2,3-triazol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 204

LCMS-ESI (POS.) m/z: 567.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.54(d, J = 7.91 Hz, 1 H), 7.12-8.03 (m, 7 H), 4.78- 5.03 (m, 1 H),4.41-4.56 (m, 1 H), 3.82-4.05 (m, 4 H), 3.43-3.71 (m, 3 H), 3.03-3.04(m, 1 H), 2.23- 2.38 (m, 1 H), 1.79-2.00 (m, 3 H), 1.57-1.74 (m, 2 H),0.70-0.96 (m, 3 H) A 1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1S)-1-(2-fluoro-4- (trifluoromethyl)phenyl)propyl)-D-prolinamide 205

LCMS-ESI (POS.) m/z: 503.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.23- 8.51 (m, 1 H), 7.68-8.00 (m, 4 H), 6.87-7.18 (m, 3 H), 4.62-5.01(m, 1 H), 4.24-4.52 (m, 1 H), 3.95- 4.07 (m, 2 H), 3.82-3.92 (m, 2 H),3.43-3.70 (m, 3 H), 2.20-2.30 (m, 1 H), 1.72-1.92 (m, 3 H), 1.05- 1.42(m, 3 H) A 1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-1-(3,5-difluorophenyl)ethyl)-D-prolinamide 206

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3-dichlorobenzyl)-D- prolinamide LCMS-ESI(POS.) m/z: 528.1 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.44 (brt, J = 5.75 Hz, 1 H), 7.39 (dd, J = 7.93, 1.61 Hz, 1 H), 7.26 (dd, J =7.67, 1.55 Hz, 1 H), 7.15-7.20 (m, 1 H), 4.53-4.64 (m, 2 H), 4.42-4.50(m, 1 H), 4.07- 4.14 (m, 4 H), 3.73-3.80 (m, 2 H), 3.53-3.60 (m, 2 H),3.38-3.48 (m, 1 H), 2.98 (dd, J = 12.70, 11.04 Hz, 1 H), 2.64-2.82 (m, 2H), 2.40-2.48 (m, 1 H), 2.08-2.22 (m, 1 H), 1.99-2.08 (m, 1 H),1.78-1.96 (m, 3 H), 1.45- 1.72 (m, 3 H) A 207

(1R,3R,5R)-N-((R)-(4-chloro-2-fluorophenyl)(3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 507.1 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.39 (t, J = 1.7 Hz, 1 H),8.09-8.15 (m, 2 H), 7.78 (t, J = 7.8 Hz, 1 H), 7.34 (t, J = 8.2 Hz, 1H), 7.25 (ddt, J = 2.2, 4.4, 8.1 Hz, 2 H), 5.58 (d, J = 10.2 Hz, 1 H),4.99 (dd, J = 4.2, 11.4 Hz, 1 H), 4.84 (dd, J = 6.5, 7.7 Hz, 1 H),4.59-4.69 (m, 2 H), 4.37 (t, J = 6.2 Hz, 1 H), 3.47- 3.58 (m, 1 H), 3.19(s, 3 H), 2.66 (dddd, J = 1.1, 6.5, 11.6, 13.3 Hz, 1 H), 1.91 (dd, J =4.2, 13.5 Hz, 1 H), 1.76- 1.84 (m, 1 H), 1.24-1.29 (m, 1 H), 0.90 (dtd,J = 1.0, 5.7, 9.1 Hz, 1 H). A 208

LCMS-ESI (POS.) m/z: 583.2 (M + Na)⁺ 1H NMR (500 MHz, CHLOROFORM- d) δppm 7.29-7.81 (m, 9 H), 5.26 (br d, J = 3.11 Hz, 1 H), 4.25-4.91 (m, 2H), 3.70 (br d, J = 13.75 Hz, 1 H), 3.10 (br t, J = 12.59 Hz, 1 H),1.15-2.47 (m, 19 H), 0.26-0.83 (m, 5 H) C(2R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(-1,1,1-trifluoro-2-hydroxy-2-propanyl)benzoyl)-2- piperidinecarboxamide 209

(3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-N-((2R)-1- LCMS-ESI (POS.) m/z:570.2 (M + Na)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.34-8.64 (m, 1 H),7.53- 7.67 (m, 3 H), 5.06-5.24 (m, 1 H), 4.59-4.92 (m, 1 H), 4.02-4.13(m, 2 H), 3.90-4.00 (m, 2 H), 3.73- 3.84 (m, 1 H), 3.51-3.67 (m, 2 H),2.94 (s, 2 H), 2.72-2.92 (m, 3 H), 1.67- 1.88 (m, 2 H), 1.47-1.62 (m, 1H), 1.32-1.42 (m, 4 H), 1.19-1.30 (m, 4 H) C (((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)amino)-1-oxo-2-propanyl)-N-methyl-3-piperidinecarboxamide 210

1-(((3S)-1-((3-((4-chlorobenzyl)oxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 643.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (d, J = 8.04 Hz, 2 H),7.28-7.48 (m, 5 H), 7.25 (br s, 2 H), 4.59 (br d, J = 6.49 Hz, 1 H),4.47-4.56 (m, 1 H), 4.39- 4.45 (m, 3 H), 4.29 (quin, J = 5.90 Hz, 1 H),3.89- 3.96 (m, 2 H), 3.85 (dd, J = 8.30, 5.45 Hz, 2 H), 3.73- 3.81 (m, 2H), 3.54-3.62 (m, 2 H), 2.91 (t, J = 11.81 Hz, 1 H), 2.64-2.76 (m, 2 H),2.44 (ddd, J = 9.15, 6.29, 3.50 Hz, 1 H), 2.12-2.32 (m, 1 H), 1.97-2.08(m, 1 H), 1.83-1.95 (m, 2 H), 1.77 (br d, J = 13.23 Hz, 1 H), 1.59-1.69(m, 1 H), 1.45- 1.54 (m, 1 H) M 211

LCMS-ESI (POS.) m/z: 551.2 (M + H)⁺ 1H NMR (500 MHz, DMSO- d6) δ ppm8.40-8.78 (m, 1 H), 7.47-8.19 (m, 7 H), 4.10-5.00 (m, 2 H), 3.17-3.79(m, 1 H), 2.86-2.98 (m, 1 H), 2.54 (s, 2 H), 1.51-1.77 (m, 2 H),−0.23-1.28 (m, 11 H) H (1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3- (cyclopropylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 212

N+190R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(3-(ethylsulfonyl)benzoyl)-D-prolinamide LCMS-ESI (POS.) m/z: 527.2 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.41- 8.80 (m, 1H), 7.47-8.02 (m,7H), 4.47-4.66 (m, 1 H), 4.07-4.39 (m, 1H), 3.12-3.64 (m, 6 H), 2.69 (s,1 H), 2.11-2.32 (m, 1 H), 1.62-1.96 (m, 3 H), 1.16-1.29 (m, 1 H), 1.12(q, J = 7.35 Hz, 3 H), 0.95 (dt, J = 8.24, 4.31 Hz, 1 H), 0.52-0.66 (m,1 H), 0.42- 0.43 (m, 1 H), 0.42-0.52 (m, 1 H), 0.32-0.44 (m, 1 H),−0.07-0.15 (m, 1 H) C 213

(1R,3R,5R)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-(3-(2-methyl-2-propanyl)benzoyl)-2- LCMS- APCI (POS.) m/z: 519.2 (M + H)⁺1H NMR (400 MHz, Methanol-d4) δ ppm 7.88 (t, 1 H), 7.54-7.60 (m, 4 H),7.48-7.53 (m, 1H), 7.42 (t, J = 0.5, 7.8 Hz, 1 H), 5.66 (d, J = 10.1 Hz,1 H), 5.00 (dd, J = 4.1, 11.3 Hz, 1 H), 4.83-4.86 (m, 1 H), 4.61-4.69(m, 2 H), 4.41 (t, 1 H), 3.49-3.60 (m, 1 H), 3.30 (dt, J = 3.2, 6.3 Hz,1 H), 2.58-2.68 (m, 1 H), 1.91 (dd, J = 4.2, 13.5 Hz, 1 H), 1.72-1.80(m, 1 H), 1.38 (s, 10 H), 1.23 (td, J = 2.6, 5.2 Hz, 1 H), 0.82-0.88 (m,1 H). A azabicyclo[3.1.0]hexane-3-carboxamide 214

LCMS-ESI (POS.) m/z: 498.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.83- 9.24 (m, 2 H), 8.28-8.80 (m, 2 H), 7.68-7.82 (m, 1 H), 7.36-7.64(m, 1 H), 4.00-5.05 (m, 2 H), 3.34- 3.41 (m, 4 H), 2.56-2.76 (m, 1 H),1.53-1.79 (m, 2 H), −0.28-1.24 (m, 7 H) C(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 215

LCMS-ESI (POS.) m/z: 498.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.76- 9.02 (m, 1 H), 8.46-8.67 (m, 1 H), 7.98-8.23 (m, 2 H), 7.40-7.66(m, 2 H), 4.16-5.06 (m, 2 H), 3.63- 3.82 (m, 2 H), 3.38 (br s, 3 H),2.12-2.28 (m, 1 H), 1.67-1.92 (m, 3 H), 1.00- 1.33 (m, 1 H), −0.04-0.57(m, 4 H) C N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-1-((6-(methylsulfonyl)-3-pyridinyl)carbonyl)-D- prolinamide 216

(4R)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-fluoro-N-(4- LCMS-ESI (POS.) m/z: 546.2 (M + H)⁺1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.47-7.56 (m, 2 H), 7.25- 7.35 (m,2 H), 6.24-6.89 (m, 1 H), 5.16-5.36 (m, 1 H), 4.67-4.74 (m, 1 H),4.38-4.50 (m, 2 H), 3.98 4.07 (m, 4 H), 3.58-3.90 (m, 4 H), 3.31-3.40(m, 1 H), 2.86-2.98 (m, 2 H), 2.55-2.74 (m, 2 H), 2.09- 2.23 (m, 1 H),1.79-1.89 (m, 1 H), 1.73 (br d, J = 13.49 Hz, 1 H), 1.45- 1.66 (m, 2 H)M (trifluoromethyl)benzyl)-D-prolinamide 217

(1R,3R,5R)-2-(2-(ethylamino)benzoyl)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS- APCI(POS.) m/z: 506.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.77 (d, J =8.0 Hz, 1 H), 7.70 (d, J = 10.3 Hz, 1 H), 7.55- 7.66 (m, 2 H), 7.17-7.31(m, 2 H), 6.55-6.68 (m, 2 H), 5.72 (t, 1 H), 5.50 (t, J = 8.8 Hz, 1 H),4.92 (dd, J = 11.2 Hz, 1 H), 4.66 (t, J+32 7.0 Hz, 1 H), 4.52 (t, J+327.0 Hz, 1 H), 4.43 (t, J+32 6.2 Hz, 1 H), 4.23 (t, J+32 6.1 Hz, 1 H),3.10 (q, J+32 4.0, 5.3 Hz, 3 H), 1.73 (dd, J = 13.4 Hz, 1 H), 1.57 (p, 1H), 1.17 (t, J = 7.1 Hz, 2 H), 0.93 (s, 1 H), 0.64 (dd, J = 5.7, 13.9Hz, 1 H). Q 218

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 510.0 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.83- 9.25 (m, 2 H), 8.25-8.72 (m, 2H), 7.54-7.68 (m, 1 H), 7.29-7.54 (m, 1 H), 4.65-4.99 (m, 1 H), 4.01-4.56 (m, 1 H), 3.33-3.40 (m, 4 H), 2.54-2.76 (m, 1 H), 1.56-1.78 (m, 2H), 0.68-1.19 (m, 3 H), −0.32- 0.60 (m, 3 H) C 219

(1R,3R,5R)-2-(3-fluoro-5- (methylsulfonyl)benzoyl)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 559.1 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (d, J = 8.1 Hz, 1 H), 7.96-8.01 (m, 1 H), 7.90 (q, J = 1.6 Hz, 1 H), 7.80 (td, J = 0.8, 1.6 Hz, 1H), 7.70 (d, J = 9.9 Hz, 1 H), 7.55-7.66 (m, 2 H), 5.44-5.55 (m, 1 H),4.90 (dd, J = 3.6, 11.4 Hz, 1 H), 4.65 (dd, J = 6.3, 7.7 Hz, 1 H), 4.52(dd, J = 6.2, 7.8 Hz, 1 H), 4.41 (t, J = 6.1 Hz, 1 H), 4.23 (t, J+32 6.2Hz, 1 H), 3.25 (s, 3 H), 2.46-2.50 (m, 3 H), 1.63- 1.78 (m, 2 H), 1.15(td, J = 2.5, 5.0 Hz, 1 H), 0.68- 0.82 (m, 1 H). Q 220

LCMS-ESI (POS.) m/z: 581.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.47(br d, J = 8.56 Hz, 1 H), 7.46- 7.97 (m, 7 H), 4.89 (br t, J = 8.37 Hz,1 H), 4.55 (br dd, J = 7.72, 5.77 Hz, 1 H), 4.29-4.37 (m, 1 H), 3.82-4.06 (m, 4 H), 3.45-3.69 (m, 4 H), 2.13-2.33 (m, 1 H), 1.80-1.90 (m, 3H), 0.58-1.01 (m, 6 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-D-prolinamide 221

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,4-difluorobenzyl)-D- LCMS-ESI (POS.) m/z:496.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.25- 8.70 (m, 1 H),7.22-7.40 (m, 2 H), 7.02-7.11 (m, 1 H), 4.16-4.52 (m, 3 H), 4.00-4.12(m, 2 H), 3.87- 3.97 (m, 2 H), 3.73-3.84 (m, 1 H), 3.37-3.69 (m, 4 H),2.67-2.92 (m, 2 H), 2.02-2.33 (m, 2 H), 1.86- 1.99 (m, 3 H), 1.72-1.85(m, 2 H), 1.38-1.55 (m, 2 H) A prolinamide 222

N-((R)-(4-chloro-2,5- difluorophenyl)(cyclopropyl)methyl)-1-((4-LCMS-ESI (POS.) m/z: 498.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.80(br d, J = 5.06 Hz, 1 H), 8.47- 8.68 (m, 1 H), 7.96-8.23 (m, 2 H),7.37-7.62 (m, 2 H), 4.15-5.04 (m, 2 H), 3.62-3.85 (m, 2 H), 3.39 (br s,3 H), 2.09-2.29 (m, 1 H), 1.65-1.92 (m, 3 H), 1.03-1.25 (m, 1 H), −0.03-0.63 (m, 4 H) C (methylsulfonyl)-2-pyridinyl)carbonyl)-D- prolinamide223

LCMS-ESI (POS.) m/z: 539.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.46- 8.79 (m, 1 H), 7.50-8.06 (m, 7 H), 4.17-4.64 (m, 2 H), 2.83-3.66(m, 3 H), 2.14-2.31 (m, 1 H), 1.62- 1.95 (m, 3 H), −0.05-1.28 (m, 10 H)H N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(3-(cyclopropylsulfonyl)benzoyl)-D-prolinamide 224

N-((R)-(4-chloro-2,5- difluorophenyl)(cyclopropyl)methyl)-1-(3-sulfamoylbenzoyl)-D-prolinamide LCMS-ESI (POS.) m/z: 498.0 (M + H)⁺ 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 8.05-8.15 (m, 1 H), 8.01 (s, 1 H),7.94-8.05 (m, 1 H), 7.73 (s, 1 H), 7.66- 7.77 (m, 1 H), 7.54-7.64 (m, 1H), 7.40-7.50 (m, 1 H), 7.05-7.19 (m, 2 H), 5.34-5.79 (m, 2 H), 4.65-4.79 (m, 1 H), 4.41-4.57 (m, 1 H), 3.93-4.39 (m, 2 H), 3.59-3.87 (m, 1H), 3.38-3.54 (m, 1 H), 1.94- 2.29 (m, 3 H), 1.80-1.92 (m, 1 H),1.05-1.28 (m, 1 H), 0.48-0.65 (m, 2 H), 0.18-0.48 (m, 2 H) C 225

(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 534.2 (M +H)⁺ 1H NMR (DMSO-d6) δ: 9.15 (d, J = 4.9 Hz, 1H), 8.96 (d, J = 7.4 Hz,1H), 8.20 (s, 1H), 8.03-7.95 (m, 1H), 7.81 (dd, J = 11.1, 5.6 Hz, 1H),5.14 (dd, J = 11.4, 3.5 Hz, 1H), 4.73 (t, J = 7.9 Hz, 1H), 2.05-1.88 (m,3H), 1.51-1.35 (m, 2H), 1.29 (td, J = 5.1, 2.6 Hz, 1H), 1.02-0.87 (m,2H), 0.79 (t, J = 8.8 Hz, 1H), 0.68 (t, J = 9.1 Hz, 1H), 0.58 (s, 2H) Q226

3-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-((4-(trifluoromethyl)benzyl)amino)ethyl)benzamide LCMS- APCI (NEG.) m/z:507.1 (M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm 7.94- 8.03 (m, 2 H),7.73-7.91 (m, 2 H), 7.61-7.67 (m, 2 H), 7.41-7.56 (m, 2 H), 5.05-5.17(m, 1 H), 4.30- 4.62 (m, 3 H), 4.03-4.17 (m, 2 H), 3.84-3.99 (m, 2 H),3.43-3.61 (m, 1 H), 2.95-3.09 (m, 3 H), 1.43- 1.62 (m, 3 H). Q 227

LCMS-ESI (POS.) m/z: 570.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.83-9.04 (m, 1H), 8.31-8.77 (m, 1H), 7.60-7.77 (m, 2H), 7.38- 7.53 (m,2H), 6.56-6.74 (m, 1H), 4.26-4.51 (m, 3H), 4.10-4.24 (m, 2H), 3.86- 4.04(m, 3H), 3.51-3.72 (m, 4H), 2.71-2.92 (m, 2H), 2.60-2.71 (m, 1H), 2.06-2.38 (m, 1H), 1.63-1.99 (m, 5H), 1.35-1.55 (m, 2H) J1-(((3S)-1-((3-(1,2-oxazol-3-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 228

N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(2-LCMS- APCI (POS.) m/z: 542.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.90 (d, J = 7.6 Hz, 1 H), 7.60- 7.77 (m, 4 H), 7.54 (s, 2 H), 6.76 (d,J = 8.8 Hz, 2 H), 6.63 (d, J = 5.2 Hz, 1 H), 4.55-4.70 (m, 3 H), 3.10(s, 3 H), 2.82 (d, J = 4.8 Hz, 3 H), 2.19-2.30 (m, 2 H), 1.62-1.80 (m, 4H), 1.15-1.31 (m, 2 H), 0.96 (d, J = 6.5 Hz, 2 H), 0.59 (d, J = 8.8 Hz,1 H), 0.39 (s, 3 H). S (methylamino)-5-(methylsulfonyl)benzoyl)-D-prolinamide 229

LCMS-ESI (POS.) m/z: 588.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.22(d, J = 8.69 Hz, 1 H), 7.52- 7.70 (m, 3 H), 4.85 (br t, J = 8.50 Hz, 1H), 4.35- 4.51 (m, 1 H), 3.73-4.10 (m, 5 H), 3.30-3.66 (m, 4 H),2.70-2.86 (m, 2 H), 2.58-2.67 (m, 1 H), 1.66- 2.12 (m, 7 H), 1.28-1.58(m, 2 H), 0.70-0.99 (m, 6 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-D- prolinamide 230

(1R,3R,5R)-2((5-(cyclobutylamino)-2-methyl-4-pyridinyl)carbonyl)-N-((R)-cyclopropyl(2-fluoro-4- LCMS- APCI (POS.)m/z: 531.2 (M + H)⁺ 1H NMR (400 MHz, Methylene Chloride- d2) δ ppm 8.00(s, 1 H), 7.44-7.54 (m, 2 H), 7.36-7.43 (m, 2 H), 6.65 (d, J = 6.7 Hz, 1H), 5.05 (dd, J = 2.8, 11.2 Hz, 1 H), 4.49 (dd, J = 6.6, 9.3 Hz, 1 H),3.94 (q, J = 7.6 Hz, 1 H), 3.11 (td, J = 2.6, 6.2 Hz, 1 H), 2.59-2.66(m, 1 H), 2.47 (ddd, J = 3.4, 7.2, 12.9 Hz, 2 H), 2.16 (dd, J = 2.7,13.4 Hz, 1 H), 1.80-2.03 (m, 4 H), 1.74 (dt, J = 5.9, 9.1 Hz, 1 H),1.26-1.35 (m, 1 H), 0.97 (ddd, J = 2.7, 5.1, 6.2 Hz, 1 H), 0.67-0.77 (m,2 H), 0.56-0.64 (m, 1 H), 0.47 (ddt, J = 4.7, 9.5, 22.4 Hz, 2 H). S(trifluoromethyl)phenyl)methyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide231

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 500.1 (M +H)⁺ 1H NMR (DMSO-d6) δ: 9.18 (d, J = 4.9 Hz, 1H), 8.90 (d, J = 7.6 Hz,1H), 8.23(s, 1H), 7.92-7.85 (m, 1H), 7.73 (dd, J = 9.8, 6.3 Hz, 1H),5.15 (dd, J = 11.4, 3.5 Hz, 1H), 4.74 (t, J = 8.0 Hz, 1H), 3.52 (td, J =6.1, 2.6 Hz, 1H), 2.03- 1.90 (m, 3H), 1.51-1.38 (m, 1H), 1.37-1.28 (m,1H), 1.03-0.93 (m, 2H), 0.85-0.74 (m, 1H), 0.74- 0.66 (m, 1H), 0.62-0.51(m, 2H) Q 232

N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3- LCMS- APCI (POS.) m/z:529.1 (M + H)⁺ 1 H NMR (400 MHz, Methanol-d4) δ ppm 8.23 (t, 1 H),8.07-8.14 (m, 1 H), 7.96 (dt, J = 1.3, 7.7 Hz, 1 H), 7.72-7.81 (m, 25.25-5.76 (m, 1 H), 4.88- 4.94 (m, 1 H), 4.65-4.72 (m, 2 H), 4.53-4.61(m, 1 H), 4.43 (t, J = 6.2 Hz, 1 H), 4.07 (dt, J = 6.2, 34.7 Hz, 1 H),3.68-3.78 (m, 1 H), 3.49-3.67 (m, 3 H), 2.33 (dtd, J = 5.8, 9.7, 10.4,12.4 Hz, 1 H), 1.94-2.06 (m, 1H), 1.80-1.94 (m, 3 H). Aoxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)- D-prolinamide 233

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((4-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 516.1 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (d, J = 5.1 Hz, 1 H), 8.72 (d,J = 5.1 Hz, 1 H), 8.64 (d, J = 8.3 Hz, 1 H), 8.45 (d, J = 8.3 Hz, 1 H),8.00-8.06 (m, 1 H), 7.95-8.00 (m, 1 H), 7.85-7.91 (m, 1 H), 7.65 (ddd, J= 6.3, 9.5, 18.0 Hz, 2 H), 7.46 (dd, J = 6.2, 9.7 Hz, 1 H), 7.28 (dd, J= 6.4, 9.8 Hz, 1 H), 5.36- 5.53 (m, 2 H), 5.12 (t, J = 9.1 Hz, 1 H),4.88 (dd, J = 3.3, 11.3 Hz, 1 H), 4.65 (dd, J = 6.3, 7.7 Hz, 1 H), 4.52(dd, 1 H), 4.33-4.44 (m, 2 H), 4.22 (t, J = 6.1 Hz, 1 H), 3.92 (td, J =3.2, 6.3 Hz, 1 H), 3.84 (td, J = 3.2, 6.1 Hz, 3 H), 3.58- 3.65 (m, 2 H),3.37-3.46 (m, 1 H), 3.19-3.29 (m, 1 H), 2.64-2.82 (m, 2 H), 1.82 (dd, J= 2.9, 13.4 Hz, 1 H), 1.75-1.79 (m, 1 H), 1.72 (dd, J = 3.4, 13.3 Hz, 1H), 1.51-1.69 (m, 2 H), 1.02-1.11 (m, 1 H), 0.73- 0.81 (m, 1 H),0.64-0.70 (m, 1 H). Q 234

1-((3-((3,3-dimethyl-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS- APCI (NEG.) m/z: 522.2 (M −H) 1H NMR (400 MHz, Methanol-d4) δ ppm 8.10 (t, J = 1.7 Hz, 1 H), 7.96(dd, J = 1.6, 7.7 Hz, 2 H), 7.73-7.82 (m, 1 H), 7.62 (d, J = 8.1 Hz, 2H), 7.55 (t, J = 9.2 Hz, 2 H), 4.55- 4.64 (m, 2 H), 4.47 (d, J = 15.9Hz, 1 H), 3.68 (dt, J = 6.9, 10.2 Hz, 1 H), 3.54 (ddd, J = 4.5, 7.0,10.2 Hz, 1 H), 3.47 (s, 4 H), 2.31- 2.48 (m, 1 H), 1.99-2.09 (m, 2 H),1.92 (ddd, J = 3.5, 7.0, 14.2 Hz, 1 H), 1.04 (s, 6 H). Q 235

LCMS-ESI (POS.) m/z: 527.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.23- 8.50 (m, 1 H), 7.70-8.06 (m, 3 H), 7.41-7.67 (m, 4 H), 4.74-5.14(m, 1 H), 4.33-4.55 (m, 1 H), 3.39- 3.61 (m, 2 H), 3.22-3.29 (m, 3 H),2.50 (d, J = 28.16 Hz, 1 H), 2.12-2.30 (m, 1 H), 1.31-2.10 (m, 9 H) AN-((R)-cyclobutyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 236

(3S)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-3-(trifluoromethyl)-L-prolinamide LCMS-ESI (POS.) m/z: 600.0 (M + H)⁺ 1HNMR (500 MHz, CHLOROFORM-d) δ ppm 9.27 (s, 1 H), 9.05 (s, 1 H), 8.41 (s,1 H), 7.43 (br d, J = 6.23 Hz, 1 H), 7.35 (dd, J = 9.41, 5.64 Hz, 1 H),7.20 (dd, J = 9.93, 5.51 Hz, 1 H), 4.93 (d, J = 5.06 Hz, 1 H), 4.48 (dd,J = 8.76, 6.68 Hz, 1 H), 3.71-3.79 (m, 1 H), 3.64-3.71 (m, 1 H), 3.48-3.61 (m, 1 H), 3.18 (s, 3 H), 2.35-2.45 (m, 1 H), 2.12-2.22 (m, 1 H),1.19- 1.29 (m, 1 H), 0.65-0.72 (m, 1 H), 0.58-0.65 (m, 1 H), 0.41-0.50(m, 2 H) C 237

1-(((3S)-1-((3-(2-fluoroethoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z:583.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.49 (br t, J = 5.96 Hz,1H), 7.35- 7.46 (m, 2H), 7.31 (d, J = 9.95 Hz, 1H), 4.58-4.64 (m, 2H),4.42-4.58 (m, 3H), 4.25-4.36 (m, 1H), 3.96- 4.04 (m, 2H), 3.88 (dd, J =5.18, 8.40 Hz, 2H), 3.75- 3.84 (m, 2H), 3.68-3.73 (m, 1H), 3.55-3.66 (m,3H), 2.94 (dd, J = 11.14, 12.70 Hz, 1 H), 2.64-2.82 (m, 2H), 2.38-2.50(m, 1H), 2.08-2.22 (m, 1H), 1.98- 2.08 (m, 1H), 1.74-1.96 (m, 3H),1.48-1.74 (m, 3H) J 238

LCMS-ESI (POS.) m/z: 516.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.43- 8.69 (m, 1 H), 6.98-8.11 (m, 7 H), 4.08-4.54 (m, 7 H), 3.39-3.71(m, 2 H), 2.17-2.34 (m, 1 H), 1.73- 2.01 (m, 3 H) CN-(4-chloro-3-fluorobenzyl)-1-(3-((3,3-difluoro-1-azetidinyl)sulfonyl)benzoyl)-D-prolinamide 239

1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(4- LCMS-ESI (POS.) m/z: 529.2 (M + H)⁺ 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.49-7.65 (m, 3 H), 7.28- 7.47 (m, 2 H),6.77 (s, 1 5.31 (s, 1 H), 4.36- 4.60 (m, 4 H), 3.93-4.19 (m, 6 H),3.69-3.89 (m, 3 3.41-3.66 (m, 4 H), 3.12-3.24 (m, 1 H), 2.84- 3.00 (m, 3H), 2.37-2.65 (m, 1 H), 1.95-2.20 (m, 5 H) M(trifluoromethyl)benzyl)-D-prolinamide 240

(4R)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-hydroxy-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 544.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.50-7.66 (m, 3 H), 7.38 (br s,2 H), 4.69 (br d, J = 7.66 Hz, 1 H), 4.55- 4.64 (m, 1 H), 4.52 (br s, 1H), 4.41 (br d, J = 14.53 Hz, 1 H), 3.99-4.17 (m, 4 H), 3.60-3.81 (m, 4H), 3.42 (br s, 1 H), 2.93 (br t, J = 11.16 Hz, 1 H), 2.76 (br t, J =11.42 Hz, 1 H), 2.60 (br s, 1 H), 2.31-2.44 (m, 1 H), 2.19 (br s, 1 H),1.23- 1.98 (m, 5 H) M 241

N-((R)-cyclopropyl(2,5-difluoro-4- (trifluoromethyl)phenyl)methyl)-1-(5-(methylsulfonyl)nicotinoyl)-3-(trifluoromethyl)pyrrolidine-2-carboxamide LCMS-ESI (POS.) m/z: 600.0(M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.27 (t, J = 2.08 Hz, 1H), 9.03 (dd, J = 17.00, 1.95 Hz, 1 H), 8.26-8.46 (m, 1 H), 7.38-7.59(m, 1 H), 7.29- 7.38 (m, 1 H), 7.09-7.23 (m, 1 H), 4.91-5.05 (m, 1 H),4.40-4.55 (m, 1 H), 3.47-3.82 (m, 3 H), 3.18 (d, J = 5.06 Hz, 3 H),2.32- 2.47 (m, 1 H), 2.06-2.23 (m, 1 H), 1.14-1.31 (m, 1 H), 0.55-0.79(m, 2 H), 0.37-0.53 (m, 2 H) C 242

LCMS-ESI (POS.) m/z: 516.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.94- 8.53 (m, 1 H), 6.68-7.30 (m, 3 H), 5.18-5.37 (m, 1 H), 4.22-4.46(m, 1 H), 4.03-4.12 (m, 2 H), 3.88- 3.97 (m, 2 H), 3.77 (br d, J = 3.24Hz, 4 H), 3.49- 3.70 (m, 4 H), 2.59-2.96 (m, 5 H), 1.64-2.41 (m, 8 H),1.32-1.57 (m, 2 H) A (2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)pyrrolidine-2- carboxamide 243

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-methylbenzyl)-D- prolinamide LCMS-ESI (POS.)m/z: 474.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.12 (s, 4 H),4.57 (dd, J = 8.04, 1.82 Hz, 1 H), 4.31- 4.44 (m, 2 H), 4.04-4.16 (m, 4H), 3.75 (br d, J = 12.72 Hz, 2 H), 3.50- 3.67 (m, 2 H), 3.37-3.50 (m, 1H), 2.96 (dd, J = 12.46, 11.16 Hz, 1 H), 2.65-2.84 (m, 2 H), 2.43 (ddd,J = 12.20, 6.49, 3.11 Hz, 1 H), 2.30-2.36 (m, 3 H), 2.12-2.30 (m, 2 H),1.97-2.10 (m, 2 H), 1.76- 1.97 (m, 4 H), 1.46-1.72 (m, 5 H) C 244

Diastereomer #1-(1R,3R,5R)-N-((2-fluoro-4-(trifluoromethyl)phenyl)(5-oxopyrrolidin-3-yl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 568.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.55-8.76 (m, 1H), 8.17- 8.38(m, 1H), 8.00-8.16 (m, 2H), 7.64-7.94 (m, 1H), 7.33-7.53 (m, 3H), 6.74-7.00 (m, 1H), 5.45-5.86 (m, 1H), 5.17-5.40 (m, 1H), 3.40-3.57 (m, 1H),3.29- 3.40 (m, 1H), 3.21-3.29 (m, 1H), 3.14 (s, 3H), 3.06-3.12 (m, 1H),2.43-2.53 (m, 1H), 2.31-2.43 (m, 2H), 2.09- 2.22 (m, 1H), 1.73-1.83 (m,1H), 1.38-1.45 (m, 1H), 0.89-0.99 (m, 1H) C 245

LCMS-ESI (POS.) m/z: 524.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.10(d, J = 8.30 Hz, 1 H), 6.78- 7.19 (m, 3 H), 4.61-4.77 (m, 1 H),4.26-4.52 (m, 1 H), 3.99-4.12 (m, 2 H), 3.91-3.97 (m, 2 H), 3.82 (br d,J = 7.40 Hz, 2 H), 3.28- 3.63 (m, 4 H), 2.58-2.91 (m, 3 H), 1.43-2.09(m, 9 H), 0.80-0.94 (m, 3 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(3,5-difluorophenyl)propyl)-D-prolinamide 246

LCMS-ESI (POS.) m/z: 539.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.73(br d, J = 7.40 Hz, 1 H), 7.49- 8.14 (m, 7 H), 4.10-5.03 (m, 2 H),3.55-3.67 (m, 1 H), 3.17-3.35 (m, 3 H), 2.53-2.60 (m, 1 H), 1.48- 1.78(m, 2 H), 1.17-1.30 (m, 1 H), 1.03-1.12 (m, 3 H), −0.22-0.76 (m, 5 H) C(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane- 3-carboxamide 247

LCMS- APCI (POS.) m/z: 612.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 7.18- 7.66 (m, 7 H), 3.92-4.47 (m, 6 H), 3.27-3.57 (m, 2 H),2.47-2.56 (m, 1 H), 2.06-2.19 (m, 1H), 1.61- 1.82 (m, 3 H), 1.05-1.17(m, 1 H), 0.79-0.98 (m, 4 H),-0.21-0.55 (m, 4 H). WN-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(3-(1-(cyclopropylsulfonyl)-3-fluoro-3- azetidinyl)benzoyl)-D-prolinamide 248

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(difluoromethyl)phenyl)ethyl)-D-prolinamide LCMS-ESI (POS.) m/z: 524.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.15- 8.71 (m, 1 H), 7.48-7.59(m, 2 H), 7.33-7.44 (m, 2 H), 6.76-7.16 (m, 1 H), 4.86-5.01 (m, 1 H),4.30- 4.49 (m, 1 H), 4.05-4.14 (m, 2 H), 3.93-4.00 (m, 2 H), 3.75-3.87(m, 1 H), 3.52-3.60 (m, 3 H), 3.29- 3.42 (m, 1 H), 2.70-2.88 (m, 2 H),2.60-2.67 (m, 1 H), 2.01-2.32 (m, 1 H), 1.65-1.92 (m, 5 H), 1.39- 1.55(m, 2 H), 1.29-1.39 (m, 3 H) A 249

(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-((2-hydroxyethyl)sulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS- APCI (POS.) m/z: 555.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.74 (d, J = 7.5 Hz, 1 H), 8.15 (t, J = 1.7 Hz, 1 H), 7.96-8.06 (m, 2H), 7.77 (t, J = 7.8 Hz, 1 H), 7.66 (dd, J = 7.3, 15.5 Hz, 3 H), 4.96(dd, J = 3.4, 11.5 Hz, 1 H), 4.87 (t, J = 5.4 Hz, 1 H), 4.58 (t, J = 7.8Hz, 1 H), 4.35 (t, J = 5.1 Hz, 1 H), 3.70 (q, J = 6.2 Hz, 2 H), 3.50 (t,J = 6.2 Hz, 2 H), 3.20-3.26 (m, 1 H), 1.63-1.75 (m, 2 H), 1.14-1.22 (m,2 H), 0.67-0.77 (m, 2 H), 0.56 (d, 1 H), 0.47 (d, J = 8.4 Hz, 1 H), 0.35(d, J = 4.6 Hz, 2 H). Q 250

1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-cyanobenzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 478.2 (M + H)⁺ 1H NMR(500 MHz, CHLOROFORM-d) δ ppm 7.96-8.02 (m, 1 H), 7.90- 7.96 (m, 1 H),7.78-7.82 (m, 1 H), 7.66-7.72 (m, 1 H), 7.57-7.64 (m, 2 H), 7.36-7.44(m, 2 H), 7.26- 7.31 (m, 1 H), 4.71-4.79 (m, 1 H), 4.48-4.58 (m, 2H),4.11-4.19 (m, 2 H), 3.96-4.05 (m, 2 H), 3.55- 3.65 (m, 1 H),3.43-3.51 (m, 1 H), 3.32-3.42 (m, 1 H), 2.43-2.54 (m, 1 H), 2.05-2.20(m, 2 H), 1.83- 1.95 (m, 1 H) A 251

LCMS- APCI (POS.) m/z: 537.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 7.75- 9.01 (m, 4 H), 7.10-7.66 (m, 4 H), 4.80 (dd, J = 7.6, 9.8 Hz,1 H), 4.59-4.69 (m, 1 H), 3.74-4.54 (m, 7 H), 3.46-3.58 (m, 1 H),3.41-3.46 (m, 1 H), 2.32- 2.44 (m, 1 H), 2.08-2.19 (m, 1 H). C(4S)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-4-hydroxy-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 252

N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(3-LCMS- APCI (POS.) m/z: 503.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.62 (dd, J = 7.6, 65.3 Hz, 1 H), 7.76 -7.90 (m, 1 H), 7.55-7.76 (m, 2H), 4.49-4.62 (m, 1 H), 4.14-4.37 (m, 1 H), 3.39-3.63 (m, 2 H), 2.14-2.27 (m, 1 H), 1.65-1.88 (m, 2 H), 0.91-1.27 (m, 2 H), 0.54 (dd, J =8.5, 35.9 Hz, 1 H), 0.33-0.41 (m, 1 H),-0.08-0.11 (m, 1 H). A(trifluoromethyl)benzoyl)-D-prolinamide 253

(2R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2-piperidinecarboxamide LCMS-ESI (POS.) m/z:527.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.96-8.11 (m, 2 H),7.56- 7.80 (m, 2 H), 7.41-7.52 (m, 2 H), 7.37 (d, J = 10.47 Hz, 1 H),7.03-7.19 (m, 1 H), 5.14-5.34 (m, 1 H), 4.47-4.64 (m, 1 H), 3.51- 3.73(m, 1 H), 3.14-3.28 (m, 1 H), 2.98-3.13 (m, 3 H), 2.21-2.32 (m, 1 H),1.63-1.92 (m, 4 H), 1.47- 1.58 (m, 1 H), 1.20-1.36 (m, 1 H), 0.64-0.73(m, 1 H), 0.54-0.64 (m, 1 H), 0.34-0.52 (m, 2 H) C 254

N-((lR)-1-(4-chloro-2-fluorophenyl)ethyl)-1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-D-prolinamide LCMS-ESI (POS.) m/z: 527.2 (M + Na)⁺1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.34 (br d, J = 7.26 Hz, 1 H),7.19-7.26 (m, 1 H), 7.04- 7.15 (m, 2 H), 5.13 (quin, J = 7.10 Hz, 1 H),4.45- 4.55 (m, 1 H), 4.08-4.18 (m, 5 H), 3.76-3.94 (m, 1 H), 3.65-3.74(m, 2 H), 3.41-3.63 (m, 4 H), 3.15 (br d, J = 13.48 Hz, 1 H), 2.75-2.98(m, 3 H), 2.27- 2.42 (m, 1 H), 2.06-2.20 (m, 1 H), 1.95-2.04 (m, 1 H),1.72-1.95 (m, 2 H), 1.43 (d, J = 7.05 Hz, 3 H) M 255

N-((R)-(4-chloro-3-fluorophenyl)(3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)- D-prolinamide LCMS- APCI(POS.) m/z: 495.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.23 (t,J = 1.6 Hz, 1 H), 8.05- 8.12 (m, 2 H), 7.96 (dt, J = 1.3, 7.7 Hz, 1 H),7.73- 7.79 (m, 1 H), 7.48 (t, 1 H), 7.25 (dd, J = 2.0, 10.2 Hz, 1 H),7.17 (dt, J = 1.3, 8.2 Hz, 1 H), 5.41 (d, J = 10.3 Hz, 1 H), 4.63-4.70(m, 2 H), 4.53-4.58 (m, 1 H), 4.46 (t, J = 6.3 Hz, 1 H), 3.62-3.70 (m, 1H), 3.47- 3.58 (m, 2 H), 3.19 (s, 4 H), 2.27-2.38 (m, 1 H), 1.96-2.05(m, 1 H), 1.79- 1.95 (m, 3 H). A 256

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,4-dimethylbenzyl)-D- prolinamide LCMS-ESI(POS.) m/z: 488.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.04- 8.44(m, 1 H), 7.03-7.09 (m, 1 H), 6.90-6.98 (m, 2 H), 4.27-4.52 (m, 1 H),4.10-4.26 (m, 2 H), 4.01- 4.09 (m, 2 H), 3.88-3.97 (m, 2 H), 3.74-3.83(m, 1 H), 3.34-3.69 (m, 4 H), 2.70-2.87 (m, 2 H), 2.19- 2.25 (m, 6 H),2.01-2.12 (m, 1 H), 1.69-1.99 (m, 6 H), 1.33-1.57 (m, 2 H) A 257

1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(3,4-dichlorobenzyl)-D- LCMS-ESI (POS.) m/z:529.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.32- 7.46 (m, 3H),7.06-7.19 (m, 1H), 4.55-4.67 (m, 1H), 4.30-4.47 (m, 2H), 4.01- 4.24 (m,5H), 3.78-3.90 (m, 1H), 3.66-3.78 (m, 2H), 3.39-3.66 (m, 3H), 3.10- 3.22(m, 1H), 2.75-3.02 (m, 3H), 2.39-2.55 (m, 1H), 2.12-2.25 (m, 1H), 1.86-2.01 (m, 2H) E prolinamide 258

LCMS-ESI (POS.) m/z: 526.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.47- 8.72 (m, 1 H), 7.60-8.04 (m, 6 H), 7.14-7.55 (m, 2 H), 3.85-4.55(m, 6 H), 3.59 (br s, 1 H), 3.39-3.51 (m, 3 H), 2.98-3.09 (m, 3 H),2.19-2.34 (m, 1 H), 1.77-2.02 (m, 3 H) C 1-((3-((3-methoxy-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 259

LCMS-ESI (POS.) m/z: 496.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.13- 8.48 (m, 1 H), 6.88-7.98 (m, 7 H), 4.33-4.77 (m, 2 H), 3.40-3.67(m, 2 H), 2.56-2.75 (m, 6 H), 2.15- 2.34 (m, 1 H), 1.32-1.95 (m, 5 H),0.43-0.94 (m, 3 H) A N-((1R)-1-(4-chloro-3-fluorophenyl)propyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide 260

N-((6-chloro-3-pyridinyl)methyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D- prolinamide LCMS-ESI (POS.)m/z: 488.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.29-8.34 (m, 1H), 7.98- 8.05 (m, 1 H), 7.93-7.96 (m, 1 H), 7.81-7.87 (m, 1 H),7.68-7.75 (m, 1 H), 7.62-7.68 (m, 1 H), 7.33- 7.41 (m, 1 H), 7.29 (d, J= 8.17 Hz, 1 H), 4.71- 4.80 (m, 1 H), 4.40-4.57 (m, 2 H), 4.14-4.23 (m,2 H), 4.04 (t, J = 7.33 Hz, 2 H), 3.60-3.68 (m, 1 H), 3.45-3.52 (m, 1H), 3.34- 3.43 (m, 1 H), 2.42-2.55 (m, 1 H), 2.10-2.19 (m, 2 H),1.88-1.95 (m, 1 H) A 261

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (difluoromethyl)benzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 510.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.45 (br d, J = 7.79 Hz, 2 H), 7.36 (br s, 1 H), 7.32 (br d, J = 7.78Hz, 2 H), 6.62 (t, J = 56.44 Hz, 1 H), 4.59 (br d, J = 6.88 Hz, 1 H),4.49 (br dd, J = 15.25, 6.16 Hz, 1 H), 4.40 (br dd, J = 15.18, 5.32 Hz,1 H), 4.02-4.16 (m, 4 H), 3.75 (br d, J = 12.46 Hz, 2 H), 3.51-3.63 (m,2 H), 3.37-3.47 (m, 1 H), 2.85- 3.03 (m, 1 H), 2.64-2.80 (m, 2 H),2.37-2.49 (m, 1 H), 2.11-2.23 (m, 1 H), 1.99-2.08 (m, 1 H), 1.86- 1.95(m, 2 H), 1.79 (br d, J = 13.49 Hz, 1 H), 1.57- 1.68 (m, 1 H), 1.42-1.56(m, 1 H). C 262

LCMS-ESI (POS.) m/z: 516.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.60- 9.03 (m, 2 H), 8.15-8.28 (m, 1 H), 7.99-8.10 (m, 1 H), 7.33-7.67(m, 2 H), 5.28-5.39 (m, 1 H), 4.49- 4.78 (m, 1 H), 3.98-4.18 (m, 2 H),3.65 (br dd, J = 14.01, 2.72 Hz, 1 H), 3.35-3.46 (m, 3 H), 2.52- 2.69(m, 1 H), 1.81-2.03 (m, 1 H), 0.89-1.34 (m, 1 H), − 0.16-0.68 (m, 4 H) C(4S)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-4-fluoro-1-((6-(methylsulfonyl)-3-pyridinyl)carbonyl)-D- prolinamide 263

(1R,3R,5R)-2-(3-(1-amino-2-methyl-1-oxo-2-propanyl)benzoyl)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 532.2 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 7.87 (t, 1 H), 7.65 (dt, J =1.2, 7.6 Hz, 1 H), 7.57 (ddd, J = 1.2, 2.0, 7.9 Hz, 1 H), 7.48 (t, 1 H),7.39 (dd, J = 6.1, 9.5 Hz, 1 H), 7.28 (dd, J = 6.3, 9.4 Hz, 1 H), 5.56(d, J = 10.2 Hz, 1 H), 4.97 (dd, J = 4.2, 11.4 Hz, 1 H), 4.83 (dd, J =6.5, 7.6 Hz, 1 H), 4.67 (dd, J = 6.4, 7.8 Hz, 1 H), 4.60 (t, J = 6.2 Hz,1 H), 4.38 (t, J = 0.9, 12.4 Hz, 1 H), 3.46-3.55 (m, 1 H), 3.37 (s, 3H), 2.59- 2.68 (m, 1 H), 1.91 (dd, J = 4.2, 13.5 Hz, 1 H), 1.77 (dq, J =5.9, 9.0 Hz, 1 H), 1.60 (d, J = 4.2 Hz, 6 H), 1.23 (td, J = 2.6, 5.3 Hz,1 H), 0.89 (dt, J = 5.8, 8.1 Hz, 1 H). V 264

(1R,3R,5R)-N-((R)-(4-chloro-3-fluorophenyl)(3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 507.1 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.39 (t, J = 1.6 Hz, 1 H), 8.09-8.15 (m, 2 H), 7.79 (t, 1 H), 7.48 (t, J = 7.6, 8.2 Hz, 1 H), 7.23 (dd,J = 2.0, 10.2 Hz, 1 H), 7.13-7.17 (m, 1 H), 5.30-5.36 (m, 1 H), 5.00(dd, J = 4.2, 11.4 Hz, 1 H), 4.83 (dd, J = 6.5, 7.7 Hz, 1 H), 4.66 (dd,J = 6.4, 7.9 Hz, 1 H), 4.60 (t, J = 6.2 Hz, 1 H), 4.42 (t, J = 6.3 Hz, 1H), 3.47 (dddd, J = 1.7, 6.0, 7.8, 10.1 Hz, 1 H), 3.19 (s, 3 H), 2.61-2.73 (m, 1 H), 1.91 (dd, 1 H), 1.77-1.86 (m, 1 H), 1.29 (td, J = 2.7,5.3 Hz, 1 H), 0.91 (dtd, J = 1.0, 5.7, 9.0 Hz, 1 H). A 265

LCMS- APCI (NEG.) m/z: 513.2 (M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm8.47 (s, 1 H), 7.84-8.02 (m, 4 H), 7.69-7.84 (m, 2 H), 7.33 (d, J = 4.6Hz, 7 H), 5.23 (s, 1 H), 5.06 (d, J = 7.3 Hz, 2 H), 4.10 (td, J = 2.8,8.9 Hz, 4 H), 3.78- 3.98 (m, 4 H), 3.49 (s, 4 H), 2.12-2.34 (m, 2 H),1.82-2.00 (m, 1H), 1.61- 1.82 (m, 4 H), 1.40-1.61 (m, 9 H). Q(2R)-N-((1S)-1-(4-chlorophenyl)ethyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-2- piperidinecarboxamide266

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 500.1(M +H)⁺ 1H NMR (DMSO-d6) δ: 9.14 (d, J = 5.1 Hz, 1H), 8.96 (d, J = 5.1 Hz,1H), 8.78 (d, J = 7.7 Hz, 1H), 8.66 (d, J = 8.0 Hz, 1H), 8.20-8.16 (m,1H), 8.14 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 4.8 Hz, 1H), 7.81 (dd, J =9.5, 6.2 Hz, 1H), 7.76 (dd, J = 9.4, 6.3 Hz, 1H), 7.69 (dd, J = 9.9, 6.3Hz, 1H), 7.60 (dd, J = 9.9, 6.3 Hz, 1H), 5.62 (dd, J = 11.5, 2.8 Hz,1H), 5.10 (dd, J = 11.4, 3.3 Hz, 1H), 4.69 (t, J = 7.9 Hz, 2H), 4.29 (t,J = 8.5 Hz, 2H), 4.15-4.06 (m, 1H), 4.00 (td, J = 6.3, 2.5 Hz, 1H), 2.01(dd, J = 13.4, 2.9 Hz, 2H), 1.91 (dd, J = 13.3, 3.2 Hz, 1H), 1.83 (s,1H), 1.75 (s, 1H), 1.43- 1.32 (m, 2H), 0.99-0.87 (m, 2H), 0.86-0.79 (m,1H), 0.72 (d, J = 9.0 Hz, 1H), 0.64 (t, J = 8.6 Hz, 1H), 0.53 (s, 1H),0.49 (d, J = 8.1 Hz, 2H) Q 267

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((2-(difluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 598.1 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.81 (d, J = 0.7, 5.0 Hz, 1 H),8.01 (s, 1 H), 7.87 (ddt, J = 0.9, 1.7, 5.1 Hz, 1 H), 7.39 (dd, J = 6.1,9.5 Hz, 1 H), 7.27 (dd, J = 6.3, 9.4 Hz, 1 H), 6.82 (t, J = 55.1 Hz, 1H), 5.57 (d, J = 10.2 Hz, 1 H), 4.96 (dd, J = 4.1, 11.4 Hz, 1 H), 4.84(dd, J = 6.5, 7.7 Hz, 1 H), 4.67 (dd, J = 6.5, 7.8 Hz, 1 H), 4.61 (t, J= 6.2 Hz, 1 H), 4.38 (t, 1 H), 3.46-3.56 (m, 1 H), 3.29 (ddd, J = 2.6,5.9, 6.6 Hz, 1 H), 2.68 (td, J = 6.3, 12.4 Hz, 1 H), 1.90 (dd, J = 4.1,13.5 Hz, 1 H), 1.77- 1.84 (m, 1 H), 1.26 (td, J = 2.6, 5.3 Hz, 1 H),0.88 (ddd, J = 5.0, 6.1, 8.3 Hz, 1 H). A 268

LCMS-ESI (POS.) m/z: 570.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.65- 9.10 (m, 1 H), 7.17-7.46 (m, 9 H), 6.02-6.14 (m, 1 H), 4.38-4.55(m, 1 H), 3.87-4.11 (m, 4 H), 3.72- 3.83 (m, 1 H), 3.33-3.65 (m, 4 H),2.59-2.88 (m, 3 H), 2.03-2.30 (m, 1 H), 1.68-1.95 (m, 5 H), 1.32- 1.55(m, 2 H) A (2R)-N-((4-chlorophenyl)(phenyl)methyl)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)pyrrolidine-2-carboxamide 269

(4S)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-4-fluoro-1-((4-(methylsulfonyl)-2-pyridinyl)carbonyl)-D- LCMS-ESI (POS.) m/z: 516.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.85- 9.03 (m, 1 H), 8.67-8.81(m, 1 H), 8.16-8.28 (m, 1 H), 8.02-8.11 (m, 1 H), 7.36-7.66 (m, 2 H),4.55- 5.42 (m, 2 H), 3.90-4.21 (m, 2 H), 3.61-3.76 (m, 1 H), 3.38-3.39(m, 3 H), 2.56-2.67 (m, 1 H), 1.82- 2.05 (m, 1 H), 1.00-1.25 (m, 1 H),0.31-0.62 (m, 3 H), − 0.17-0.11 (m, 1 H) C prolinamide 270

(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3- (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 525.0 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.33 (s, 1 H), 8.09 (d, J =7.88 Hz, 1 H), 8.01 (d, J = 7.67 Hz, 1 H), 7.71 (t, J = 7.77 Hz, 1 H),7.62 (br d, J = 7.46 Hz, 1 H), 7.28- 7.48 (m, 3 H), 5.11 (br d, J = 9.12Hz, 1 H), 4.60 (t, J = 7.98 Hz, 1 H), 3.22- 3.29 (m, 1 H), 3.11 (s, 3H), 2.61 (br d, J = 13.27 Hz, 1 H), 2.29 (td, J = 11.82, 6.22 Hz, 1 H),1.66-1.78 (m, 1 H), 1.10-1.33 (m, 3 H), 0.83-0.89 (m, 1 H), 0.46-0.61(m, 2 H), 0.33- 0.43 (m, 2 H) C 271

1-(((2S,3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-2-methyl-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 542.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.56 (d, J = 8.04 Hz, 2 H),7.43 (br t, J = 5.58 Hz, 1 H), 7.35 (d, J = 8.04 Hz, 2 H), 4.40-4.56 (m,3 H), 4.24 (quin, J = 6.10 Hz, 1 H), 3.98-4.16 (m, 4 H), 3.60- 3.75 (m,3 H), 3.34-3.43 (m, 1 H), 2.99-3.08 (m, 1 H), 2.88-2.96 (m, 1 H), 2.41(ddd, J = 9.02, 6.42, 3.24 Hz, 1 H), 2.12-2.28 (m, 1 H), 1.88-2.09 (m, 3H), 1.75 (br d, J = 13.49 Hz, 1 H), 1.49-1.68 (m, 2 H), 1.19-1.29 (m, 3H) M 272

N-(3-chloro-4-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- LCMS-ESI (POS.) m/z:512.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.32 (s, 1 H), 7.18-7.51(m, 3 H), 5.85-5.85 (m, 1 H), 4.17- 4.49 (m, 3 H), 4.00-4.14 (m, 2 H),3.87-4.00 (m, 2 H), 3.73-3.86 (m, 1 H), 3.50-3.73 (m, 3 H), 3.33- 3.49(m, 1 H), 2.61-2.91 (m, 3 H), 2.04-2.33 (m, 1 H), 1.65-1.98 (m, 5 H),1.34-1.59 (m, 2 H) A prolinamide 273

(4S)-4-fluoro-N-((R)-(3-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide LCMS- APCI (POS.) m/z: 547.1 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.25 (t, J = 1.8 Hz, 1 H), 8.11-8.16 (m, 1 H), 7.98 (dt, J = 1.3, 7.7 Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1 H), 7.35 (d, J = 10.6 Hz, 2 H), 5.47-5.52 (m,1 H), 5.33-5.41 (m, 1 H), 5.18-5.28 (m, 1 H), 4.77 (dd, J = 7.5, 10.2Hz, 1 H), 4.65-4.71 (m, 2 H), 4.49 (t, J = 6.3 Hz, 1 H), 3.91-4.07 (m, 1H), 3.72 (ddd, J = 2.2, 12.7, 19.9 Hz, 1 H), 3.54 (dddd, J = 1.7, 6.0,7.7, 10.1 Hz, 1 H), 3.37 (s, 2 H), 3.19 (s, 4 H), 2.53-2.67 (m, 1 H),2.04- 2.23 (m, 1 H). A 274

LCMS-ESI (POS.) m/z: 553.2 (M + Na)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.22- 8.80 (m, 1 H), 7.57-7.82 (m, 2 H), 7.45 (br d, J = 7.79 Hz, 2 H),6.06-6.46 (m, 1 H), 4.26-4.56 (m, 3 H), 3.37-3.99 (m, 8 H), 3.03- 3.24(m, 1 H), 2.59-2.93 (m, 3 H), 1.67-2.40 (m, 6 H), 1.32-1.58 (m, 2 H)1-(((3S)-1-( (3-(difluoromethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 275

(1R,3R,5R)-2-(3-(ethylsulfonyl)benzoyl)-N-((R)-3-oxetanyl(4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 537.2 (M +H)⁺ 1H NMR (Methanol-d4) δ: 8.76 (d, J = 8.2 Hz, 1H), 8.35 (t, J = 1.7Hz, 1H), 8.13 (d, J = 7.7, 1.4 Hz, 1H), 8.08 (d, J = 7.9, 1.9, 1.2 Hz,1H), 7.79 (t, J = 8.1, 7.6 Hz, 1H), 7.73- 7.66 (m, 2H), 7.52 (d, J = 8.1Hz, 2H), 5.47-5.37 (m, 1H), 5.01 (dd, J = 11.4, 4.2 Hz, 1H), 4.86-4.82(m, 1H), 4.72-4.57 (m, 2H), 4.44 (t, J = 6.3 Hz, 1H), 3.59-3.41 (m, 1H),3.31-3.24 (m, 3H), 2.68 (td, J = 12.7, 6.6 Hz, 2H), 1.92 (dd, J = 13.5,4.2 Hz, 2H), 1.87-1.73 (m, 2H), 0.97-0.83 (m, 2H) C 276

LCMS-ESI (POS.) m/z: 516.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.93- 8.51 (m, 1 H), 6.98-7.46 (m, 4 H), 5.14-5.35 (m, 1 H), 4.67-4.88(m, 1 H), 4.20-4.51 (m, 1 H), 3.85- 4.13 (m, 4 H), 3.69-3.84 (m, 2 H),3.41-3.70 (m, 5 H), 3.10-3.21 (m, 1 H), 2.60-2.97 (m, 4 H), 1.33- 2.30(m, 9 H) A (2R)-1-((S)-1-( (3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(3-(hydroxymethyl)-2,3-dihydro-1H-inden-1- yl)pyrrolidine-2-carboxamide 277

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(((3S)-1-(methylsulfonyl)-3-piperidinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 516.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.69 (br d, J = 6.62 Hz, 1 H),7.05-7.18 (m, 2 H), 4.85 (br d, J = 10.12 Hz, 1 H), 4.42-4.51 (m, 1 H),3.97 (br d, J = 11.42 Hz, 1 H), 3.89 (br d, J = 11.29 Hz, 1 H),3.41-3.55 (m, 1 H), 2.99-3.17 (m, 1 H), 2.88- 2.98 (m, 1 H), 2.77-2.87(m, 3 H), 2.69 (br t, J = 11.35 Hz, 1 H), 2.48- 2.63 (m, 1 H), 2.12-2.30(m, 2 H), 1.93 (br d, J = 13.49 Hz, 1 H), 1.77- 1.86 (m, 1 H), 1.70-1.77(m, 1 H), 1.60-1.69 (m, 1 H), 1.14 (br dd, J = 7.66, 3.89 Hz, 1 H),0.89-0.97 (m, 1 H), 0.83 (br d, J = 7.79 Hz, 1 H), 0.48-0.68 (m, 2 H),0.34 (br d, J = 3.24 Hz, 1 H), 0.26-0.43 (m, 1 H) M 278

LCMS-ESI (POS.) m/z: 509.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.37- 8.70 (m, 1 H) 7.90-8.21 (m, 3 H) 7.68-7.81 (m, 1 H) 7.14-7.33 (m,2 H) 4.65-4.99 (m, 1 H) 3.79- 4.27 (m, 1 H) 3.24-3.28 (m, 4 H) 2.54-2.62(m, 1 H) 1.55-1.82 (m, 2 H) 0.69-1.17 (m, 3 H) 0.09- 0.56 (m, 4 H) C(1R,3R,5R)-N-((R)-(4-chloro-3,5-difluorophenyl)(cyclopropyl)methyl)-2-(3- (methylsulfonyl)benzoyl)-2-azabicyc1o[3.1.0]hexane-3-carboxamide 279

LCMS-ESI (POS.) m/z: 544.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.94(d, J = 4.80 Hz, 1 H), 8.75 (d, J = 7.40 Hz, 1 H), 7.83- 8.27 (m, 2 H),7.69-7.81 (m, 1 H), 7.59 (dd, J = 11.03, 5.45 Hz, 1 H), 4.11-5.04 (m, 2H), 3.19- 3.37 (m, 4 H), 2.54-2.76 (m, 1 H), 1.53-1.83 (m, 2 H),−0.22-1.30 (m, 7 H) C (1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyc1o[3.1.0]hexane-3-carboxamide 280

(4S)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-4-fluoro-1-(3-sulfamoylbenzoyl)-D-prolinamide LCMS-ESI (POS.) m/z: 516.0 (M + H)⁺ 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 8.16 (s, 1 H), 8.06 (d, J = 7.98 Hz, 1H), 7.76 (d, J = 7.77 Hz, 1 H), 7.50- 7.66 (m, 2 H), 7.03-7.20 (m, 2 H),5.42-6.13 (m, 2 H), 5.12-5.31 (m, 1 H), 4.92 (t, J = 8.40 Hz, 1 H),4.42-4.53 (m, 1 H), 3.68- 3.94 (m, 2 H), 2.41-2.62 (m, 2 H), 0.88-1.27(m, 1 H), −0.11-0.63 (m, 4 H) C 281

LCMS-ESI (POS.) m/z: 581.1 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.43- 8.79 (m, 1 H), 7.50-8.21 (m, 7 H), 4.87-5.24 (m, 2 H), 4.12-4.70(m, 2 H), 3.33-3.70 (m, 2 H), 2.14- 2.31 (m, 1 H), 1.57-2.01 (m, 3 H),0.76-1.37 (m, 1 H),-0.16-0.76 (m, 4 H) C N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-((2,2,2-trifluoroethyl)sulfonyl)benzoyl)-D-prolinamide 282

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 516.1 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 9.12- 9.18 (m, 1 H), 8.53 (dd, J =8.0, 113.7 Hz, 1 H), 8.24- 8.37 (m, 1 H), 7.65 (ddd, J = 6.2, 9.4, 18.7Hz, 1 H), 7.44 (dd, J = 6.3, 9.7 Hz, 1 H), 5.41 (t, J = 8.9 Hz, 1 H),4.90 (dd, J = 3.8, 11.4 Hz, 1 H), 4.63 (dd, 1 H), 4.51 (dd, 1 H), 4.37(t, J = 6.1 Hz, 1 H), 4.20 (t, J = 6.1 Hz, 1 H), 3.37 (td, J = 2.7, 6.3Hz, 1 H), 2.54- 2.64 (m, 1 H), 1.66-1.78 (m, 1 H), 1.11-1.20 (m, 1 H),0.80 (dt, J = 5.6, 9.9 Hz, 1 H). Q 283

1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-cyclopropylbenzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 493.0 (M + H)⁺ 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 7.98-8.06 (m, 1 H), 7.91- 7.97 (m, 1H), 7.81-7.88 (m, 1 H), 7.66-7.72 (m, 1 H), 7.15-7.22 (m, 2 H), 7.05 (s,2 H), 6.96 (br t, J = 5.05 Hz, 1 H), 4.66- 4.76 (m, 1 H), 4.39-4.52 (m,2 H), 4.10-4.20 (m, 2 H), 4.01-4.08 (m, 2 H), 3.60-3.68 (m, 1 H), 3.44-3.52 (m, 1 H), 3.35-3.38 (m, 1 H), 2.35-2.49 (m, 1 H), 2.12-2.23 (m, 2H), 1.85-1.97 (m, 2 H), 0.94- 1.03 (m, 2 H), 0.66-0.75 (m, 2 H) A 284

N-(2-chloro-4-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- LCMS-ESI (POS.) m/z:512.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.18- 8.70 (m, 1 H),7.16-7.45 (m, 3 H), 4.18-4.54 (m, 3 H), 4.00-4.11 (m, 2 H), 3.89-3.98(m, 2 H), 3.75- 3.85 (m, 2 H), 3.41-3.59 (m, 3 H), 2.70-2.91 (m, 2 H),2.58-2.68 (m, 1 H), 2.04-2.33 (m, 1 H), 1.62- 2.00 (m, 5 H), 1.31-1.55(m, 2 H) A prolinamide 285

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4- methylphenyl)ethyl)-D-prolinamideLCMS-ESI (POS.) m/z: 488.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.15-7.25 (m, 4 H), 7.04- 7.14 (m, 1 H), 5.02 (s, 1 H), 4.53 (dd, J =7.98, 2.79 Hz, 1 H), 4.08-4.20 (m, 4 H), 3.74-3.85 (m, 2 H), 3.59-3.71(m, 2 H), 3.42- 3.50 (m, 1 H), 2.97-3.08 (m, 1 H), 2.71-2.86 (m, 2 H),2.34-2.41 (m, 3 H), 2.17-2.33 (m, 2 H), 1.82- 2.12 (m, 4 H), 1.59-1.77(m, 2 H), 1.39-1.51 (m, 3 H) A 286

LCMS- APCI (POS.) m/z: 586.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 7.18- 7.63 (m, 7 H), 4.12-4.47 (m, 6 H), 3.28-3.56 (m, 2 H),2.87-2.91 (m, 3 H), 2.06-2.20 (m, 1 H), 1.60- 1.82 (m, 3 H), 0.79-1.17(m, 1 H),-0.22-0.57 (m, 4 H). W N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(3-fluoro-1-(methylsulfonyl)-3-azetidinyl)benzoyl)-D- prolinamide 287

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,5-difluorobenzyl)-D- prolinamide LCMS-ESI(POS.) m/z: 496.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.31- 8.72(m, 1 H), 7.02-7.19 (m, 1 H), 6.90-6.99 (m, 2 H), 4.22-4.54 (m, 3 H),3.98-4.12 (m, 2 H), 3.86- 3.97 (m, 2 H), 3.74-3.83 (m, 1 H), 3.42-3.72(m, 4 H), 2.81 (q, J = 11.16 Hz, 2 H), 2.61-2.75 (m, 1 H), 2.06-2.34 (m,1 H), 1.67- 2.01 (m, 5 H), 1.36-1.58 (m, 2 H) A 288

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-2- methylbenzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 492.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.15- 8.56 (m, 1 H), 7.13-7.24 (m, 1 H), 6.99-7.10 (m, 2 H), 4.17-4.50(m, 3 H), 4.01-4.10 (m, 2 H), 3.88- 3.97 (m, 2 H), 3.74-3.83 (m, 1 H),3.33-3.68 (m, 4 H), 2.70-2.87 (m, 2 H), 2.59-2.69 (m, 1 H), 2.04- 2.34(m, 4 H), 1.66-2.00 (m, 5 H), 1.34-1.56 (m, 2 H) A 289

(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((4-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 534.1 (M +H)⁺ 1H NMR (Methanol-d4) δ: 8.88 (d, J = 5.1 Hz, 1H), 8.75 (d, J = 5.1Hz, 1H), 8.12 (d, 2H), 7.80 (d, J = 5.0 Hz, 1H), 7.75 (d, 1H), 7.51-7.36(m, 3H), 7.30 (dd, J = 10.7, 5.6 Hz, 1H), 5.64 (dd, J = 11.7, 3.1 Hz,1H), 5.01 (dd, J = 11.4, 3.7 Hz, 1H), 4.48 (d, J = 9.1 Hz, 1H), 4.09 (d,J = 9.4 Hz, 1H), 4.00-3.85 (m, 2H), 2.91-2.73 (m, 1H), 2.73-2.58 (m,1H), 2.03- 1.83 (m, 2H), 1.81-1.69 (m, 1H), 1.69-1.58 (m, 1H), 1.31-1.16(m, 2H), 1.16-1.00 (m, 2H), 0.93- 0.79 (m, 2H), 0.79-0.61 (m, 2H),0.61-0.51 (m, 1H), 0.51-0.40 (m, 3H), 0.19-0.06 (m, 1H), 0.04- −0.07 (m,1H) Q 290

N-(4-chloro-2-fluorobenzyl)-1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-D- LCMS-ESI 1 (POS.) m/z:513.2 (M + Na)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.30 (m, 2 H),7.05- 7.16 (m, 2 H), 4.33-4.57 (m, 3 H), 4.09-4.17 (m, 4 H), 3.75-3.84(m, 1 H), 3.64-3.70 (m, 2 H), 3.40 3.61 (m, 3 H), 3.08-3.15 (m, 1 H),2.73-2.95 (m, 3 H), 2.38-2.45 (m, 1 H), 2.00-2.21 (m, 2 H), 1.80- 1.96(m, 3 H) M prolinamide 291

N-((1R)-1-(4-chlorophenyl)ethyl)-1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2- morpholinyl)carbonyl)-D-prolinamideLCMS-ESI (POS.) m/z: 510.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ7.29- 7.34 (m, 2H), 7.21-7.27 (m, 2H), 6.93-7.05 (m, 1H), 4.91-5.16 (m,1H), 4.49- 4.76 (m, 1H), 4.11-4.25 (m, 5H), 3.91-4.05 (m, 1H), 3.77-3.89(m, 1H), 3.63- 3.75 (m, 2H), 3.42-3.57 (m, 3H), 3.21 (br dd, J = 9.69,12.28 Hz, 1H), 3.00-3.10 (m, 1H), 2.29-2.39 (m, 1H), 2.07-2.21 (m, 1H),1.85- 2.03 (m, 2H), 1.44 (br d, J = 6.84 Hz, 3H) C 292

LCMS-ESI (POS.) m/z: 512.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm9.08- 9.23 (m, 1 H), 8.80-9.00 (m, 1 H), 8.56-8.73 (m, 1 H), 8.16-8.40(m, 1 H), 7.42-7.72 (m, 2 H), 4.23- 5.23 (m, 2 H), 3.26-3.41 (m, 4 H),2.17 (br s, 1 H), 1.66-1.80 (m, 1 H), 1.12- 1.64 (m, 6 H), 0.23-0.59 (m,4 H) C (2R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-piperidinecarboxamide 293

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(2-fluoro-4- LCMS-ESI (POS.) m/z: 574.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.27 (d, J = 8.04 Hz, 1 H),7.53- 7.69 (m, 3 H), 4.86-5.04 (m, 1 H), 4.31-4.49 (m, 1 H),4.01-4.11(m, 2 H), 3.90-3.96 (m, 2 H), 3.74- 3.82 (m, 1 H), 3.36-3.66 (m, 4 H),2.69-2.86 (m, 2 H), 2.63 (tt, J = 11.24, 3.49 Hz, 1 H), 2.07-2.21 (m, 1H), 1.82-1.97 (m, 3 H), 1.61-1.79 (m, 4 H), 1.25- 1.52 (m, 2 H),0.81-0.92 (m, 3 H) A (trifluoromethyl)phenyl)propyl)-D-prolinamide 294

LCMS-ESI (POS.) m/z: 527.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.73(d, J = 7.53 Hz, 1 H), 7.45- 8.10 (m, 7 H), 4.01-4.67 (m, 2 H),3.42-3.52 (m, 1 H), 3.23-3.33 (m, 3 H), 2.83-3.19 (m, 1 H), 2.09- 2.40(m, 2 H), 1.16-1.36 (m, 2 H), 0.80-1.04 (m, 3 H),-0.26-0.63 (m, 4 H) C(4R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-methyl-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 295

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((2- LCMS-ESI (POS.) m/z: 536.0(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.38- 9.05 (m, 2 H), 7.69-8.23(m, 2 H), 7.28-7.68 (m, 2 H), 4.60-4.99 (m, 1 H), 4.04-4.57 (m, 1 H),3.23- 3.88 (m, 1 H), 2.91-3.12 H (m, 1 H), 2.53-2.79 (m, 1 H), 1.53-1.83(m, 2 H), 1.04-1.31 (m, 5 H),-0.23- 0.97 (m, 5 H) H(cyclopropylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 296

1-(((3S)-1((3-(difluoromethyl)-3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z:587.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.41-7.47 (m, 1 H),7.28-7.41 (m, 3 H), 5.72-6.04 (m, 1 H), 4.42-4.61 (m, 3 H), 3.99-4.05(m, 2 H), 3.90-3.98 (m, 2 H), 3.69- 3.80 (m, 2 H), 3.53-3.66 (m, 2 H),3.34 (s, 1 H), 3.01 (dd, J = 12.75, 10.57 Hz, 1 H), 2.78-2.87 (m, 1 H),2.67-2.77 (m, 1 H), 2.41 (ddt, J = 12.50, 6.34, 2.97, 2.97 Hz, 1 H),2.11- 2.24 (m, 1 H), 1.98-2.09 (m, 1 H), 1.78-1.97 (m, 3 H), 1.63-1.73(m, 1 H), 1.50-1.58 (m, 1 H) J 297

LCMS-ESI (POS.) m/z: 546.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.34- 8.77 (m, 1 H), 7.41-7.68 (m, 3 H), 4.21-4.52 (m, 3 H), 4.00-4.10(m, 2 H), 3.87-3.97 (m, 2 H), 3.74- 3.83 (m, 1 H), 3.35-3.69 (m, 4 H),2.67-2.91 (m, 2 H), 1.62-2.33 (m, 7 H), 1.31-1.56 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-D-prolinamide 298

LCMS-ESI (POS.) m/z: 511.0 (M + Na)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δppm 7.58-7.99 (m, 4 H), 7.23- 7.37 (m, 4 H), 6.75-6.99 (m, 1 H),5.02-5.25 (m, 2 H), 4.12 4.24 2 H), 3.97-4.08 (m, 2 H), 3.32- 3.43 (m, 1H), 2.92-3.01 (m, 2 H), 2.75-3.01 (m, 1 H), 1.44-1.55 (m, 6 H) CN-((2R)-1-((1-(4-chlorophenyl)ethyl)amino)-1-oxopropan-2-)-3-((3-cyanoazetidin-1- yl)sulfonyl)-N-methylbenzamide 299

(2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-N-((2R)-1- (((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)amino)-1-oxo-2-propanyl)-N-methyl-2-morpholinecarboxamide LCMS-ESI (POS.) m/z: 550.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.45- 8.62 (m, 1 H), 7.54-7.70(m, 3 H), 5.07-5.22 (m, 1 H), 4.62-4.90 (m, 1 H), 4.26-4.41 (m, 1 H),4.08- 4.19 (m, 2 H), 3.97-4.07 (m, 2 H), 3.78-3.96 (m, 2 H), 3.58-3.76(m, 1 H), 3.35-3.55 (m, 2 H), 3.04 (ddd, J = 19.11, 12.16, 9.99 Hz, 1H), 2.65-2.99 (m, 4 H), 1.33-1.43 (m, 3 H), 1.25 (dd, J = 14.34, 6.94Hz, 3H) C 300

(2R)-N-((R)-cyclopropyl(3-fluoro-4- LCMS-ESI (POS.) m/z: 527.2 (M + H)⁺1H NMR (500 MHz, DMSO-d6) δ ppm 8.71 (br d, J = 2.85 Hz, 1 H), 7.98-8.04 (m, 1 H), 7.90 (s, 1 H), 7.64-7.81 (m, 3 H), 7.48 (br d, J = 10.64Hz, 1 H), 7.36-7.44 (m, 1 H), 2.94-5.28 (m, 7 H), 2.04- 2.27 (m, 1 H),1.46-1.81 (m, 3 H), 1.33-1.45 (m, 1 H), 1.08-1.25 (m, 2 H), 0.46-0.65(m, 3 H), 0.31- 0.43 (m, 1 H) C (trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2-piperidinecarboxamide 301

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(3,4-difluorophenyl)ethyl)-D-prolinamide LCMS-ESI (POS.) m/z: 510.2 (M + H)⁺1H NMR (500 MHz, DMSO-d6) δ ppm 8.58* (d, J = 7.66 Hz, 1 H), 8.18 (d, J= 7.91 Hz, 1 H), 7.27- 7.40 (m, 2 H), 7.08-7.14 (m, 1 H), 4.82-4.95 (m,1 H), 4.46* (dd, J = 8.30, 2.72 Hz, 1 H), 4.27 (dd, J = 8.50, 4.09 Hz, 1H), 4.02-4.09 (m, 2 H), 3.89-3.97 (m, 2 H), 3.74-3.84 (m, 1 H),3.51-3.64 (m, 3 H), 3.27- 3.43 (m, 1 H), 2.71-2.85 (m, 2 H), 2.60-2.68(m, 1 H), 2.30* (br t, J = 10.70 Hz, 1 H), 2.17-2.26* (m, 1 H),2.03-2.12 (m, 1 H), 1.64- 1.93 (m, 5 H), 1.38-1.55 (m, 2 H), 1.36* (d, J= 7.01 Hz, 3 H), 1.33 (d, J = 7.01 Hz, 3 H). Spectrum appears as 2:1mixture of rotamers, *denotes resolved minor rotamer peaks. C 302

LCMS-ESI (NEG.) m/z: 595.2 (M − H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.27-8.76 (m, 1H), 7.61-7.77 (m, 3H), 7.12-7.51 (m, 5H), 5.25- 5.42 (m,1H), 4.22-4.47 (m, 3H), 3.83-3.98 (m, 1H), 3.33-3.78 (m, 7H), 2.61- 2.70(m, 1H), 2.01-2.38 (m, 3H), 1.52-2.01 (m, 5H), 1.06-1.45 (m, 2H) J(2R)-1-((3S)-1-((2-(2-fluorophenyl)azetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide 303

LCMS-ESI (POS.) m/z: 468.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.61(t, J = 5.97 Hz, 1 H), 7.11- 7.96 (m, 7 H), 4.01-4.52 (m, 3 H),3.42-3.68 (m, 2 H), 3.25-3.39 (m, 3 H), 2.54-2.67 (m, 6 H), 2.18- 2.33(m, 1 H), 1.75-1.99 (m, 3 H) C N-(4-chloro-3-fluorobenzyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide 304

N-((R)-(4-chloro-2-fluorophenyl)(3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)- D-prolinamide LCMS- APCI(POS.) m/z: 595.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.22 (t,1 H), 8.04-8.12 (m, 2 H), 7.96 (dt, J = 1.3, 7.8 Hz, 1 H), 7.73-7.79 (m,1 H), 7.37 (t, J = 8.2 Hz, 1 H), 7.18-7.27 (m, 3 H), 5.65 (d, J = 10.4Hz, 1 H), 5.51 (s, 1 H), 4.68 (td, 2 H), 4.44-4.59 (m, 2 H), 4.40 (t, J= 6.2 Hz, 1 H), 3.70-3.78 (m, 1 H), 3.65 (dt, J = 7.2, 10.2 Hz, 1 H),3.49-3.60 (m, 2 H), 2.26- 2.38 (m, 1 H), 1.94-2.05 (m, 1 H), 1.80-1.93(m, 3 H). A 305

LCMS-ESI (POS.) m/z: 517.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.16- 8.47 (m, 1 H), 6.99-8.08 (m, 8 H), 4.82-4.89 (m, 1 H), 4.56-4.58(m, 1 H), 4.35-4.41 (m, 1 H), 3.79- 4.03 (m, 4 H), 3.42-3.72 (m, 5 H),2.24 (br d, J = 2.59 Hz, 1 H), 1.73-2.00 (m, 3 H) AN-((1R)-1-(4-chlorophenyl)-2-hydroxyethyl)-1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-D- prolinamide 306

((3-(((1R,3R,5R)-3-(((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)carbamo)-2- azabicyclo[3.1.0]hexan-2-yl)carbonyl)phenyl)sulfonyl)acetic acid LCMS-ESI (POS.) m/z: 587.0 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 13.28 (br d, J = 1.30 Hz, 1 H), 8.71(d, J = 7.27 Hz, 1 H), 8.39 (br d, J = 7.01 Hz, 1 H), 8.20 (s, 1 H),7.95-8.12 (m, 2 H), 7.19-7.83 (m, 4 H), 4.95 (dd, J = 11.29, 3.50 Hz, 1H), 4.43-4.68 (m, 4 H), 4.02-4.16 (m, 1 H), 3.72- 3.77 (m, 1 H), 3.22(td, J = 6.16, 2.47 Hz, 1 H), 2.52- 2.77 (m, 2 H), 1.62-1.79 (m, 2 H),1.51 (s, 1 H), 1.12-1.32 (m, 1 H), 1.00- 1.12 (m, 1 H), 0.66-0.80 (m, 1H), 0.23-0.64 (m, 4 H) O 307

LCMS-ESI (POS.) m/z: 525.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.42- 8.73 (m, 1 H) 7.89-8.22 (m, 3 H) 7.20-7.82 (m, 4 H) 4.66-5.02 (m,1 H) 3.82-4.34 (m, 1 H) 3.23- 3.28 (m, 4 H) 2.55 (s, 1 H) 1.79 (dd, J =13.30, 3.70 Hz, 1 H) 1.52-1.73 (m, 1 H) 0.67-1.18 (m, 3 H)-0.30- 0.58(m, 4 H) A (1R,3R,5R)-N-((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3- (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 308

N-((1S)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- LCMS-ESI (POS.) m/z: 562.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.97- 9.58 (m, 1 H), 7.41-7.63(m, 4 H), 5.72-5.86 (m, 1 H), 4.36-4.64 (m, 1 H), 4.01-4.11 (m, 2 H),3.88- 4.01 (m, 2 H), 3.74-3.83 (m, 1 H), 3.31-3.65 (m, 4 H), 2.72-2.92(m, 2 H), 2.59-2.70 (m, 1 H), 2.02- 2.21 (m, 1 H), 1.57-1.97 (m, 5 H),1.31-1.56 (m, 2 H) A piperidinyl)carbonyl)-D-prolinamide 309

(1R,3R,5R)-N-((R)-cyclopropyl(2-methoxy-4-(trifluoromethyl)phenyl)methyl)-2-(3- (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 537.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.25-8.43 (m, 1 H), 8.10 (br d,J = 7.78 Hz, 1 H), 8.04 (br d, J = 7.66 Hz, 1 H), 7.66- 7.81 (m, 2 H),7.32 (br d, J = 7.78 Hz, 1 H), 7.21 (br d, J = 7.53 Hz, 1 H), 7.03- 7.13(m, 1 H), 5.10 (dd, J = 10.38, 1.95 Hz, 1 H), 4.64 (br t, J = 8.50 Hz, 1H), 3.78-4.01 (m, 3 H), 3.25 (td, J = 6.07, 2.40 Hz, 1 H), 3.13 (s, 3H), 2.63 (dd, J = 13.17, 2.01 Hz, 1 H), 2.20-2.36 (m, 1 H), 1.68- 1.83(m, 1 H), 1.22-1.35 (m, 1 H), 1.09-1.21 (m, 1 H), 0.72-0.93 (m, 1 H),0.36-0.60 (m, 3 H), 0.23- 0.36 (m, 1 H) A 310

(1R,3R,5R)-N-((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3- (cyclopropylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 551.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.23-8.29 (m, 1 H), 7.96- 8.08(m, 2 H), 7.65-7.75 (m, 1 H), 7.48-7.59 (m, 2 H), 7.14-7.25 (m, 2 H),5.13-5.22 (m, 1 H), 4.26- 4.39 (m, 1 H), 3.24-3.32 (m, 1 H), 2.54-2.63(m, 1 H), 2.47-2.54 (m, 1 H), 2.35-2.45 (m, 1 H), 1.72- 1.85 (m, 1 H),1.32-1.44 (m, 2 H), 1.03-1.26 (m, 4 H), 0.85-0.96 (m, 1 H), 0.52-0.71(m, 2 H), 0.31- 0.46 (m, 2 H) H 311

LCMS-ESI (POS.) m/z: 583.2 (M + Na)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.22- 8.86 (m, 1 H), 7.56-7.83 (m, 2 H), 7.45 (br d, J = 7.79 Hz, 2 H),5.95-6.33 (m, 1 H), 4.25-4.53 (m, 5 H), 3.91-4.07 (m, 2 H), 3.51- 3.84(m, 9 H), 2.60-2.93 (m, 3 H), 1.30-2.42 (m, 10 H) M1-(((3S)-1-((3-(2,2-difluoroethoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 312

LCMS- APCI (POS.) m/z: 548.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 8.16 (t, J = 1.7 Hz, 1 H), 7.97- 8.00 (m, 2 H), 7.73-7.80 (m, 1 H),7.60-7.67 (m, 2 H), 7.54 (d, J = 8.2 Hz, 2 H), 4.80 (t, J = 7.5 Hz, 1H), 4.61 (dd, J = 4.6, 15.7 Hz, 1 H), 4.44-4.55 (m, 1 H), 3.88 (s, 4 H),3.78 (d, J = 9.9 Hz, 1 H), 2.06-2.26 (m, 2 H), 0.60 (dddd, J = 3.1, 6.1,14.3, 25.3 Hz, 4 H), 0.47 (s, 4 H). Q (6R)-5-((3-(5-azaspiro[2.3]hex-5-ylsulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-5-azaspiro[2.4]heptane-6- carboxamide 313

LCMS-ESI (Pos.) m/z: 512.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.35(br t, J = 5.97 Hz, 1 H), 6.99- 7.35 (m, 3 H), 4.32-4.36 (m, 1 H),4.24-4.29 (m, 2 H), 3.98-4.12 (m, 2 H), 3.85-3.97 (m, 2 H), 3.78 (tt, J= 8.69, 6.16 Hz, 1 H), 3.28-3.69 (m, 4 H), 2.71- 2.88 (m, 2 H),2.60-2.70 (m, 1 H), 2.06-2.31 (m, 1 H), 1.63-1.98 (m, 5 H), 1.35-1.56(m, 2 H) A N-(3-chloro-5-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 314

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((2- LCMS-ESI (POS.) m/z: 510.0(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.79- 8.99 (m, 1 H), 8.39-8.71(m, 1 H), 7.70-8.24 (m, 2 H), 7.55-7.67 (m, 1 H), 7.30-7.53 (m, 1 H),4.58- 4.97 (m, 1 H), 4.08-4.54 (m, 1 H), 3.26-3.34 (m, 4 H), 2.54-2.72(m, 1 H), 1.55-1.79 (m, 2 H),-0.24- 1.25 (m, 7 H) C(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 315

LCMS-ESI (POS.) m/z: 512.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.62(s, 1 H), 7.14-7.96 (m, 8 H), 4.13-4.53 (m, 3 H), 3.99- 4.10 (m, 1 H),3.54-3.64 (m, 1 H), 2.58-2.71 (m, 3 H), 2.14-2.36 (m, 1 H), 1.67-1.99(m, 3 H), 0.85- 1.01 (m, 7 H) C1-(3-(methyl(2-propanyl)sulfamoyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 316

(1R,3R,5R)-N-((S)-(4-chloro-2,5-difluorophenyl)(1-hydroxycyclopropyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS-ESI (POS.) m/z: 525.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.54(d, J = 8.29 Hz, 1 H), 8.15- 8.19 (m, 1 H), 7.99-8.09 (m, 2 H),7.75-7.82 (m, 1 H), 7.60-7.66 (m, 1 H), 7.44-7.52 (m, 1 H), 5.53 (s, 1H), 4.97 (dd, J = 11.30, 3.63 Hz, 1 H), 4.88 (d, J = 8.19 Hz, 1 H),3.23- 3.28 (m, 4 H), 2.52-2.62 (m, 1 H), 1.65-1.75 (m, 2 H), 1.10-1.15(m, 1 H), 0.62-0.79 (m, 4 H), 0.51- 0.58 (m, 1 H) A 317

(3S)-N-((2R)-1-(((1R)-1-(4-chloro-2-fluorophenyl)ethyl)amino)-1-oxo-2-propanyl)-1-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-3- piperidinecarboxamideLCMS-ESI (POS.) m/z: 514.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.24- 8.53 (m, 1 H), 7.33-7.44 (m, 2 H), 7.24-7.30 (m, 1 H), 5.00-5.17(m, 1 H), 4.57-4.92 (m, 1 H), 4.02- 4.12 (m, 2 H), 3.90-3.99 (m, 2 H),3.74-3.84 (m, 1 H), 3.51-3.66 (m, 2 H), 2.67-2.97 (m, 6 H), 1.66- 1.89(m, 2 H), 1.39-1.61 (m, 2 H), 1.29-1.38 (m, 4 H), 1.22 (d, J = 7.14 Hz,2 H) B 318

(2R)-N-((R)-(4-chloro-2,5- LCMS-ESI (POS.) m/z: 534.0 (M + Na)⁺ 1H NMR(500 MHz, DMSO-d6) δ ppm 8.82- 8.94 (m, 1 H), 8.53-8.76 (m, 1 H), 7.95(br d, J = 6.49 Hz, 1 H), 7.43-7.81 (m, 3 H), 5.14 (br J = 4.54 Hz, H),4.33-4.47 (m, 1 H), 3.28-3.37 (m, 4 H), 2.05 (br d, J = 12.46 Hz, 1 H),1.06-1.78 (m, 7 H), 0.25- 0.66 (m, 4 H) Cdifluorophenyl)(cyclopropyl)methyl)-1-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2- piperidinecarboxamide 319

1-(((3S)-1-(((3R)-3-cyano-1-pyrrolidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 542.2 (M + Na)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δppm 7.57 (m, J = 8.09 Hz, 2 H), 7.42 (t, J = 6.07 Hz, 1 H), 7.35 (m, J =8.09 Hz, 2 H), 4.47-4.63 (m, 2 H), 4.38- 4.46 (m, 1 H), 3.79 (br d, J =12.85 Hz, 2 H), 3.43- 3.67 (m, 6 H), 3.11-3.20 (m, 1 H), 3.01 (dd, J =12.75, 11.09 Hz, 1 H), 2.70-2.86 (m, 2 H), 2.15- 2.43 (m, 4 H),1.88-2.09 (m, 3 H), 1.62-1.84 (m, 2 H), 1.46-1.57 (m, 1 H) M 320

N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4,4-difluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide LCMS-ESI (POS.) m/z: 549.0 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.06-8.16 (m, 2 H), 7.78- 7.86(m, 1 H), 7.69-7.78 (m, 1 H), 7.40-7.54 (m, 3 H), 7.36 (d, J = 10.26 Hz,1 H), 5.01 (br t, J = 8.14 Hz, 1 H), 4.57 (br t, J = 8.03 Hz, 1 H),3.88-4.04 (m, 1 H), 3.74-3.84 (m, 1 H), 2.94- 3.20 (m, 4 H), 2.48-2.66(m, 1 H), 1.20-1.34 (m, 1 H), 0.50-0.67 (m, 2 H), 0.33-0.49 (m, 2 H) C321

N-((1R)-1-(2,4-difluorophenyl)ethyl)-1-(((3S)-1-((3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide LCMS-ESI (POS.) m/z: 563.1 (M + H)⁺1H NMR (400 MHz, CHLOROFORM-d) δ 7.22- 7.28 (m, 2H), 6.75-6.89 (m, 2H),5.08-5.23 (m, 1H), 4.56-4.79 (m, 2H), 4.47- 4.56 (m, 1H), 4.16-4.28 (m,4H), 3.90-4.00 (m, 1H), 3.76-3.84 (m, 2H), 3.58- 3.67 (m, 2H), 2.99-3.09(m, 1H), 2.93-2.97 (m, 3H), 2.81-2.91 (m, 1H), 2.71- 2.81 (m, 1H),2.22-2.32 (m, 1H), 2.09-2.21 (m, 1H), 1.94-2.06 (m, 2H), 1.58- 1.72 (m,2H), 1.39-1.48 (m, 3H) A 322

LCMS-ESI (POS.) m/z: 585.2 (M + Na)⁺ 1H NMR (500 MHz, DMSO-d6) 6 ppm8.62- 8.92 (m, 1 H), 7.30-8.14 (m, 9 H), 4.36-5.27 (m, 2 H), 3.33-3.43(m, 1 H), 1.94-2.26 (m, 1 H), 1.07- 1.84 (m, 7 H), 0.24-0.74 (m, 4 H) P(2R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzoyl)-2- piperidinecarboxamide 323

(1R,3R,5R)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-(3-methyl-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 555.2 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (d, J = 8.1 Hz, 1 H), 7.95-8.03 (m, 1 H), 7.90 (d, J = 1.6 Hz, 1 H), 7.81 (d, J = 1.7 Hz, 1 H),7.68-7.75 (m, 1 H), 7.55-7.65 (m, 2 H), 5.49 (dd, J = 8.1, 9.6 Hz, 1 H),4.90 (dd, J = 3.7, 11.3 Hz, 1 H), 4.65 (dd, J = 6.3, 7.8 Hz, 1 H), 4.52(dd, J = 6.1, 7.9 Hz, 1 H), 4.41 (t, J = 6.1 Hz, 1 H), 4.23 (t, J = 6.2Hz, 1 H), 3.41 (q, J = 7.2, 7.7 Hz, 1 H), 3.22- 3.27 (m, 4 H), 2.57 (dd,J = 6.2, 12.5 Hz, 1 H), 1.61- 1.78 (m, 3 H), 1.15 (td, J = 2.6, 5.1 Hz,1 H), 0.76 (dt, J = 5.3, 10.0 Hz, 1 H). Q 324

2-(3-((3-cyanoazetidin-1-yesulfonyl)benzoyl)-N- LCMS-ESI (POS.) m/z:583.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 9.10 (br s, 1 H), 7.98(br d, J = 7.01 Hz, 1 H), 7.90-7.95 (m, 1 H), 7.78-7.89 (m, 1 H), 7.71(br d, J = 7.79 Hz, 1 H), 7.65 (br d, J = 7.79 Hz, 2 H), 7.59 (br d, J =4.80 Hz, 1 H), 7.46 (br d, J = 7.27 Hz, 1 H), 7.25-7.30 (m, 2 H), 7.10-7.25 (m, 2 H), 5.83 (s, 1 H), 4.42 (br d, J = 5.32 Hz, 1 H), 3.97-4.10(m, 2 H), 3.77-3.94 (m, 2 H), 3.63- 3.76 (m, 1 H), 3.53-3.63 (m, 1 H),3.08-3.23 (m, 2 H), 2.93-3.06 (m, 1 H), 2.71-2.93 (m, 1 H) I(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide 325

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2,4-difluorophenyl)ethyl)-D-prolinamide LCMS-ESI (POS.) m/z: 510.2 (M + H)⁺1H NMR (500 MHz, DMSO-d6) δ ppm 8.65* (d, J = 7.40 Hz, 1 H), 8.30 (d, J= 7.53 Hz, 1 H), 7.32- 7.39 (m, 1 H), 7.14-7.21 (m, 1 H), 7.02-7.10 (m,1 H), 5.11* (quin, J = 7.04 Hz, 1 H), 5.03 (quin, J = 7.20 Hz, 1 H),4.46* (dd, J = 8.43, 2.72 Hz, 1 H), 4.29 (dd, J = 8.56, 4.02 Hz, 1 H),4.00-4.09 (m, 2 H), 3.91- 3.97 (m, 2 H), 3.79 (dtt, J = 9.23, 9.12,9.12, 6.11, 6.11 Hz, 1 H), 3.28-3.61 (m, 4 H), 2.71-2.85 (m, 2 H), 2.63(tt, J = 11.13, 3.34 Hz, 1 H), 2.28-2.35* (m, 1 H), 2.15-2.23* (m, 1 H),2.02-2.10 (m, 1 H), 1.63- 1.92 (m, 5 H), 1.37-1.54 (m, 2 H), 1.36* (d, J= 7.01 Hz, 3 H), 1.32 (d, J = 7.01 Hz, 3 H). Spectrum appears as 2:1mixture of rotamers, *denotes resolved minor rotamer peaks C 326

(1R,3R,5R)-2-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((6- LCMS-ESI (POS.) m/z:541.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.60- 8.83 (m, 1 H), 8.54(t, J = 5.97 Hz, 1 H), 7.80- 7.98 (m, 2 H), 4.27-4.83 (m, 4 H),4.00-4.13 (m, 2 H), 3.85-4.00 (m, 2H), H), 3.72-3.85 (m, 1 H), 3.42-3.72 (m, 3 H), 2.57-3.03 (m, 3 H), 1.97-2.19 (m, 1 H), 1.06-1.88 (m, 6H), 0.55-0.83 (m, 1 H) C (trifluoromethyl)-3-pyridinyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 327

1-(((3S)-1-((3-cyano-3-fluoro-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z:564.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.36- 7.48 (m, 3H),7.29-7.34 (m, 1H), 4.58-4.62 (m, 1H), 4.42-4.58 (m, 2H), 4.24- 4.38 (m,4H), 3.74-3.84 (m, 2H), 3.52-3.64 (m, 2H), 3.00 (dd, J = 10.99, 12.75Hz, 1H), 2.80 (dt, J = 2.85, 12.41 Hz, 1H), 2.71 (tt, J = 3.58, 11.20Hz, 1H), 2.36-2.49 (m, 1H), 2.11- 2.25 (m, 1H), 1.99-2.10 (m, 1H),1.79-1.97 (m, 3H), 1.63-1.74 (m, 1H), 1.49- 1.56 (m, 1H) J 328

(3R)-N-((R)-(4-chloro-2,5- LCMS-ESI (POS.) m/z: 513.0 (M + H)⁺ 1H NMR(500 MHz, DMSO-d6) δ ppm 8.58- 8.80 (m, 1 H), 8.03 (dd, J = 8.82, 1.82Hz, 1 H), 7.82 -7.92 (m, 1 H), 7.56-7.79 (m, 3 H), 7.43-7.55 (m, 1 H),3.35-5.01 (m, 7 H), 3.18-3.28 (m, 4 H), 1.09- 1.29 (m, 1 H), 0.41-0.66(m, 2 H), 0.22-0.40 (m, 2 H) C difluorophenyl)(cyclopropyl)methyl)-4-(3-(methylsulfonyl)benzoyl)-3- morpholinecarboxamide 329

LCMS-ESI (POS.) m/z: 538.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.50- 8.72 (m, 1 H), 7.60-8.03 (m, 6 H), 7.11-7.55 (m, 2 H), 4.13-4.54(m, 7 H), 3.81-4.02 (m, 4 H), 3.50- 3.67 (m, 2 H), 2.22-2.35 (m, 1 H),1.74-2.01 (m, 3 H) C 1-((3-(2-oxa-6-azaspiro[3.3]hept-6-ylsulfonyl)phenyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide330

N-((1S)-1-(4-chlorophenyl)ethyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D- prolinamide LCMS- APCI (NEG.)m/z: 499.1 (M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm 8.09 (t, J = 1.7Hz, 1 H), 7.95- 7.99 (m, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 7.37-7.46 (m,2 H), 7.26-7.33 (m, 2 H), 5.03 (q, J = 7.3 Hz, 1 H), 4.60 (dd, J = 6.1,8.0 Hz, 1 H), 4.09 (t, J = 8.7 Hz, 2 H), 3.92 (dt, J = 6.2, 8.5 Hz, 2H), 3.64 (dt, J = 6.9, 10.3 Hz, 1 H), 3.46- 3.59 (m, 2 H), 2.31-2.42 (m,1 H), 1.96-2.07 (m, 2 H), 1.83-1.94 (m, 1 H), 1.47 (d, J = 7.0 Hz, 3 H).A 331

N-((1R)-2-(((1S)-1-(4-chlorophenyl)ethyl)amino)-1-methyl-2-oxoethyl)-3-((3-cyano-1- LCMS-ESI (POS.) m/z: 511.2 (M + Na)⁺1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.88-8.01 (m, 2 H), 7.63- 7.85 (m,2 H), 7.26-7.39 (m, 4 H), 6.70-6.91 (m, 1 H), 5.11-5.21 (m, 1 H),5.03-5.11 (m, 1 H), 4.14- 4.23 (m, 1 H), 4.11-4.29 (m, 1 H), 3.96-4.08(m, 2 H), 3.33-3.46 (m, 1 H), 2.89-3.13 (m, 3 H), 1.41- 1.53 (m, 6 H) Cazetidinyl)sulfonyl)-N-methylbenzamide 332

N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-hydroxy-3-(2-propanyl)-1-azetidinyl)sulfonyl)- LCMS-ESI (POS.) m/z:579.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.44 (br t, J = 7.62 Hz,2H), 7.35- 7.40 (m, 1H), 7.31 (d, J = 9.85 Hz, 1H), 4.59 (dd, J = 2.13,8.03 Hz, 1H), 4.43- 4.56 (m, 2H), 3.72-3.88 (m, 6H), 3.55-3.63 (m, 2H),2.92-3.15 (m, 1H), 2.68- 2.84 (m, 2H), 2.39-2.48 (m, 1H), 2.09-2.24 (m,2H), 1.62-2.06 (m, 7H), 0.96 (d, J = 6.84 Hz, 6H) J3-piperidinyl)carbonyl)-D-prolinamide 333

N-(4-chloro-3-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- piperidinyl)carbonyl)-D-prolinamideLCMS-ESI (POS.) m/z: 562.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.53-7.56 (m, 1 H), 7.50 (br t, J = 5.44 Hz, 1 H), 7.44 -7.48 (m, 1 H),7.35-7.40 (m, 1 H), 4.60 (dd, J = 7.98, 2.07 Hz, 1 H), 4.54 (dd, J =15.50, 6.79 Hz, 1 H), 4.32 (dd, J = 15.50, 5.44 Hz, 1 H), 4.07-4.16 (m,4 H), 3.73-3.80 (m, 2 H), 3.54- 3.63 (m, 2 H), 3.43 (tt, J = 8.68, 6.56Hz, 1 H), 2.90 -3.03 (m, 1 H), 2.65-2.81 (m, 2 H), 2.42-2.51 (m, 1 H),2.12-2.26 (m, 1 H), 2.01-2.11 (m, 1 H), 1.85- 1.96 (m, 2 H), 1.77-1.85(m, 1 H), 1.61-1.73 (m, 1 H), 1.42-1.55 (m, 1 H) A 334

1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(3-fluoro-4- methylbenzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 493.2 (M + Na)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δppm 7.10-7.23 (m, 2 H), 6.89- 6.97 (m, 2 H), 4.58 (dd, J = 8.09, 1.87Hz, 1 H), 4.30 -4.49 (m, 2 H), 4.10-4.18 (m, 4 H), 3.77-3.96 (m, 1 H),3.65-3.71 (m, 2 H), 3.41-3.63 (m, 3 H), 3.13 (br d, J = 13.48 Hz, 1 H),2.73-2.95 (m, 3 H), 2.39- 2.49 (m, 1 H), 2.12-2.28 (m, 3 H), 2.01-2.09(m, 2 H), 1.80-1.97 (m, 2 H) M 335

LCMS-ESI (POS.) m/z: 546.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.38(br s, 1 H), 7.31-7.75 (m, 3 H), 4.25-4.44 (m, 3 H), 3.89-4.12 (m, 4 H),3.74- 3.84 (m, 1 H), 3.50-3.70 (m, 1 H), 3.26-3.48 (m, 3 H), 2.62-2.89(m, 3 H), 2.17-2.32 (m, 1 H), 1.67- 1.97 (m, 5 H), 1.35-1.57 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-3-(trifluoromethyl)benzyl)-D-prolinamide 336

LCMS-ESI (POS.) m/z: 488.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ 8.11-8.56 (m, 1 H), 7.02-7.10 (m, 1 H), 7.00 (s, 1 H), 6.89-6.97 (m, 1 H),4.11- 4.47 (m, 3 H), 3.99-4.10 (m, 2 H),3.86-3.97(m, 2 H), 3.74-3.82 (m,1 H), 3.34-3.68 (m, 4 H), 2.66- 2.85 (m, 2 H), 1.71-2.32 (m, 13 H),1.36-1.55 (m, 2 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,4-dimethylbenzyl)-D- prolinamide 337

N-((1R)-2-((4-chlorobenzyl)amino)-1-methyl-2-oxoethyl)-3-((3-cyano-1-azetidinyl)sulfonyl)-N- methylbenzamide LCMS-ESI(POS.) m/z: 475.0 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.06 (brd, J = 12.33 Hz, 1 H), 7.86-7.96 (m, 2 H), 7.61-7.73 (m, 2 H), 7.32 (d,J = 8.30 Hz, 2 H), 7.22 (d, J = 8.24 Hz, 2 H), 6.90 (br s, 1 H),5.31 (s,1 H), 5.20 (br d, J = 6.23 Hz, 1 H), 4.49 (br dd, J = 14.69, 5.81 Hz, 1H), 4.39 (dd, J = 14.86, 5.64 Hz, 1 H), 4.05-4.23 (m, 3 H), 3.97- 4.05(m, 2 H), 3.29-3.42 (m, 1 H), 3.06 (br s, 1 H), 2.92 (br s, 1 H),2.83-3.10 (m, 1 H), 2.01 (s, 1 H), 1.60 (s, 2 H), 1.51 (br d, J = 6.94Hz, 3 H), 1.32 (br dd, J = 14.69, 6.58 Hz, 1 H), 0.96-0.96 (m, 1 H) C338

LCMS-ESI (POS.) m/z: 550.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.29- 8.80 (m, 1 H), 4.16-4.47 (m, 3 H), 3.98-4.10 (m, 2 H), 3.86-3.96(m, 2 H), 3.78 (tq, J = 8.80, 5.90 Hz, 1 H), 3.45-3.64 (m, 3 H),3.36-3.44 (m, 1 H), 2.58- 2.83 (m, 3 H), 1.63-2.18 (m, 6 H), 1.29-1.56(m, 2 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(pentafluorobenzyl)-D- prolinamide 339

LCMS-ESI (POS.) m/z: 579.2 (M + Na)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.25- 8.77 (m, 1 H), 7.58-7.87 (m, 2 H), 7.06-7.55 (m, 7 H), 4.93-5.29(m, 1 H), 4.19-4.53 (m, 3 H), 3.89 (q, J = 8.56 Hz, 1 H), 3.37- 3.79 (m,4 H), 2.52-2.82 (m, 2 H), 0.91-2.45 (m, 11 H) M1-(((3S)-1-(((2R)-2-phenyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide,1-(((3S)-1-(((2S)-2-phenyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 340

(1R,2R,5S)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-3-(3-sulfamoylbenzoyl)-3-azabicyclo[3.1.0]hexane-2- carboxamide LCMS-ESI(POS.) m/z: 510.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.09 (t,J = 1.45 Hz, 1 H), 8.02 (dt, J = 7.77, 1.50 Hz, 1 H), 7.62-7.69 (m, 1H), 7.55-7.62 (m, 1 H), 7.40- 7.48 (m, 1 H), 7.08-7.22 (m, 2 H),5.41-5.69 (m, 2 H), 4.29-4.55 (m, 1 H), 3.89-4.27 (m, 1 H), 3.46- 3.82(m, 2 H), 1.70-1.79 (m, 1 H), 1.66 (dquin, J = 7.28, 3.86, 3.86, 3.86,3.86 Hz, 1 H), 1.21-1.33 (m, 1 H), 0.78-0.87 (m, 1 H), 0.52-0.72 (m, 2H), 0.29-0.49 (m, 2 H), 0.11- 0.29 (m, 1 H) C 341

3-((3-cyano-1-azetidinyl)sulfonyl)-N-((1R)-2-((3,4-dichlorobenzyl)amino)-1-methyl-2-oxoethyl)-N- methylbenzamide LCMS-ESI(POS.) m/z: 509.0 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.89-7.97 (m, 2 H), 7.70 (br s, 2 H), 7.58-7.66 (m, 1 H), 7.42 (d, J =8.24 Hz, 1 H), 7.28-7.36 (m, 1 H), 7.09-7.26 (m, 1 H), 7.03 (br s, 1 H),5.31 (s, 1 H), 5.19 (br d, J = 6.49 Hz, 1 H), 4.48 (br dd, J = 15.02,6.00 Hz, 1 H), 4.36 (dd, J = 15.18, 5.71 Hz, 1 H), 4.15 (t, J = 8.43 Hz,2 H), 4.02 (br s, 2 H), 3.31-3.43 (m, 1 H), 3.08 (br s, 1 H), 2.94 (brs, 3 H), 2.01 (s, 1 H), 1.62 (br s, 1 H), 1.52 (br d, J = 6.88 Hz, 4 H)C 342

(4S)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-1,3-thiazolidine-4-carboxamideLCMS-ESI (POS.) m/z: 532.0 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm9.19-9.36 (m, 1 H), 8.97- 9.14 (m, 1 H), 8.34-8.48 (m, 1 H), 7.40-7.50(m, 2 H), 7.33-7.40 (m, 1 H), 7.08-7.18 (m, 1 H), 4.97- 5.23 (m, 1 H),4.62-4.73 (m, 1 H), 4.41-4.60 (m, 2 H), 3.48-3.74 (m, 1 H), 3.27-3.38(m, 1 H), 3.06- 3.25 (m, 3 H), 1.27-1.37 (m, 1 H), 0.53-0.77 (m, 2 H),0.33-0.51 (m, 2 H) C 343

1-(((3S)-1-((3-(difluoromethoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- LCMS-ESI (POS.) m/z:569.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ 8.28-8.77 (m, 1H), 7.39-7.79(m, 4H), 6.49-6.95 (m, 1H), 4.86- 5.02 (m, 1H), 4.26-4.52 (m, 3H),4.01-4.17 (m, 2H), 3.75-3.85 (m, 2H), 3.51- 3.70 (m, 4H), 2.69-2.90 (m,2H), 2.60-2.69 (m, 1H), 2.03-2.38 (m, 1H), 1.65- 2.03 (m, 5H), 1.34-1.57(m, 2H) J (trifluoromethyl)benzyl)-D-prolinamide 344

(1R,3R,5R)-N-((R)-(4-chloro-2- fluorophenyl)(cyclopropyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS-ESI (POS.) m/z: 491.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.29- 8.68 (m, 1 H) 7.87-8.20 (m, 3 H) 7.23-7.81 (m, 4 H) 4.59-4.99 (m,1 H) 4.06-4.58 (m, 1 H) 3.20- 3.27 (m, 4 H) 2.51-2.59 (m, 1 H) 1.51-1.74(m, 2 H) 0.77-1.19 (m, 2 H) 0.67-0.76 (m, 1 H) 0.48- 0.56 (m, 1 H)0.38-0.46 (m, 1 H) 0.19-0.37 (m, 2 H) A 345

LCMS-ESI (POS.) m/z: 528.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.90(s, 1 H), 7.41-7.78 (m, 5 H), 6.79 (d, J = 8.69 Hz, 1 H), 6.04-6.66 (m,2 H), 4.18- 4.67 (m, 2 H), 3.53-3.60 (m, 1 H), 3.23-3.30 (m, 1 H),2.97-3.15 (m, 3 H), 2.17-2.30 (m, 1 H), 1.60- 1.90 (m, 3 H), 0.86-1.29(m, 1 H), 0.00-0.69 (m, 4 H) C1-(2-amino-5-(methylsulfonyl)benzoyl)-N-((R)- cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide 346

LCMS-ESI (POS.) m/z: 542.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.27-7.92 (m, 9 H), 7.24- 7.25 (m, 1 H), 4.62-4.76 (m, 1 H), 4.38-4.54(m, 2 H), 3.92-4.01 (m, 2 H), 3.45-3.59 (m, 4 H), 3.30- 3.43 (m, 1 H),2.74-2.90 (m, 3 H), 2.35-2.47 (m, 1 H), 1.98-2.12 (m, 2 H), 1.96-2.13(m, 2 H), 1.73- 1.89 (m, 1 H) B methyl N-methyl-N-((3-(((2R)-2-((4-(trifluoromethyl)benzyl)carbamo)-1-pyrrolidinyl)carbonyl)phenyl)sulfonyl)glycinate 347

LCMS-ESI (POS.) m/z: 569.2 (M + Na)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δppm 7.32-7.67 (m, 9 H), 7.24 (br s, 1 H), 4.20-5.36 (m, 3 H), 3.69 (brd, J = 13.23 Hz, 1 H), 3.13 (br t, J = 12.85 Hz, 1 H), 2.35- 2.77 (m, 6H), 2.25 (br d, J = 13.49 Hz, 1 H), 1.10- 1.97 (m, 8 H), 0.32-0.75 (m, 5H) C (2R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(2,2,2-trifluoro-1-hydroxyethyl)benzoyl)piperidine-2- carboxamide 348

(1R,3R,5R)-2-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 541.3 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.88 (s, 1 H), 8.51-8.81 (m, 1 H),8.11-8.21 (m, 1 H), 7.42- 7.58 (m, 1 H), 4.62-4.90 (m, 2 H), 4.36-4.52(m, 3 H), 4.00-4.14 (m, 2 H), 3.86-4.00 (m, 2 H), 3.79 (tt, J = 8.89,6.03 Hz, 1 H), 3.46-3.72 (m, 3 H), 2.64- 2.98 (m, 3 H), 2.02-2.18 (m, 1H), 1.86 (dd, J = 13.49, 3.37 Hz, 1 H), 1.60-1.82 (m, 2 H), 1.26- 1.60(m, 2 H), 0.98-1.17 (m, 1 H), 0.57-0.85 (m, 1 H) C 349

(1R,3R,5R)-2-(3-(1- carbamoylcyclopropyl)benzoyl)-N+190R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 546.2 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 7.85 (t, J = 1.7 Hz, 1 H), 7.72(dt, J = 1.5, 7.6 Hz, 1 H), 7.59 (dt, J = 1.4, 7.8 Hz, 1 H), 7.54-7.57(m, 2 H), 7.48-7.53 (m, 2 H), 5.65 (d, J = 10.1 Hz, 1 H), 5.00 (dd, J =4.1, 11.4 Hz, 1 H), 4.83-4.86 (m, 1 H), 4.61- 4.70 (m, 2 H), 4.40 (t, J= 6.2 Hz, 1 H), 3.52-3.61 (m, 1 H), 3.35-3.40 (m, 2 H), 2.59-2.69 (m, 1H), 1.92 (dd, J = 4.2, 13.5 Hz, 1 H), 1.73-1.80 (m, 1 H), 1.56 (td, J =2.0, 3.0, 3.5 Hz, 2 H), 1.22 (td, J = 2.6, 5.3 Hz, 1 H), 1.10-1.20 (m, 2H), 0.85 (dt, J = 5.9, 9.1 Hz, 1 H). V 350

1-((3-(5-azaspiro[2.3]hex-5- ylsulfonyl)phenyl)carbonyl)-N-(4- LCMS-APCI (POS.) m/z: 522.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.15(q, J = 1.5 Hz, 1 H), 7.92- 8.06 (m, 2 H), 7.71-7.83 (m, 1 H), 7.58-7.66(m, 2 H), 7.54 (d, J = 8.1 Hz, 2 H), 4.55-4.67 (m, 2 H), 4.47 (dd, J =5.1, 15.9 Hz, 1 H), 3.88 (s, 4 H), 3.69 (dt, J = 6.9, 10.3 Hz, 1 H),3.55 (ddd, J = 4.4, 6.8, 10.4 Hz, 1 H), 2.38 (ddd, J = 5.5, 8.2, 11.9Hz, 1 H), 2.04 (ddq, J = 5.9, 6.4, 12.5, 18.8 Hz, 2 H), 1.93 (ddt, J =5.6, 7.6, 10.8 Hz, 1 H), 0.47 (d, J = 1.1 Hz, 4 H). Q(trifluoromethyl)benzyl)-D-prolinamide 351

LCMS- APCI (POS.) m/z: 574.1 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm11.18 (s, 1 H), 8.76 (d, J = 8.0 Hz, 1 H), 7.64-7.75 (m, 2 H), 7.49-7.64(m, 2 H), 7.35- 7.49 (m, 1 H), 5.49 (t, J = 8.9 Hz, 1 H), 4.87 (dd, J =9.0 Hz, 1 H), 4.64 (t, 1 H), 4.51 (t, 1 H), 4.40 (t, J = 6.2 Hz, 1 H),4.22 (t, J = 6.2 Hz, 1 H), 3.15-3.23 (m, 1 H), 1.73 (dd, J = 14.4 Hz, 1H), 1.59-1.70 (m, 1 H), 0.62-0.74 (m, 1 H). Q(1R,3R,5R)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-(2-(2,2,2-trifluoroacetamido)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 352

(4S)-N-((R)-(4-chloro-2-fluorophenyl)(3- oxetanyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide LCMS- APCI (POS.) m/z: 513.1 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.25 (t, 1 H), 8.13 (ddd, J =1.1, 1.9, 7.9 Hz, 1 H), 7.95- 7.99 (m, 1 H), 7.79 (td, J = 0.5, 7.8 Hz,1 H), 7.37 (t, J = 8.2 Hz, 1 H), 7.22-7.27 (m, 2 H), 5.67 (d, J = 10.4Hz, 1 H), 5.27 (d, J = 52.0 Hz, 1 H), 4.72-4.78 (m, 1 H), 4.68 (td, J =0.9, 6.7 Hz, 2 H), 4.39 (t, J = 6.2 Hz, 1 H), 3.98 (ddd, J = 2.8, 12.6,37.4 Hz, 1 H), 3.52-3.75 (m, 2 H), 3.37 (s, 3 H), 3.20 (d, J = 4.1 Hz, 4H), 2.57 (td, J = 7.6, 15.9, 16.4 Hz, 1 H), 2.01- 2.20 (m, 1 H). A 353

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3- (trifluoromethyl)benzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 528.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.41-7.53 (m, 4 H), 4.53- 4.63 (m, 2 H), 4.37 (dd, J = 15.44, 5.45 Hz, 1H), 4.05-4.14 (m, 4 H), 3.69- 3.79 (m, 2 H), 3.51-3.64 (m, 2 H), 3.42(tt, J = 8.68, 6.57 Hz, 1 H), 2.95 (dd, J = 12.59, 11.16 Hz, 1 H),2.65-2.79 (m, 2 H), 2.44- 2.44 (m, 1 H), 2.39-2.49 (m, 1 H), 2.12-2.30(m, 1 H), 2.00-2.08 (m, 1 H), 1.83-1.94 (m, 2 H), 1.74- 1.82 (m, 1 H),1.58-1.74 (m, 1 H), 1.42-1.55 (m, 1 H), 1.36-1.97 (m, 1 H) A 354

(4R)-N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-4-(difluoromethyl)-1-(3-(methylsulfonyl)benzoyl)-D- prolinamide LCMS-ESI(POS.) m/z: 563.0 (M + H)⁺ Note: cyclopropyl methyne obscured by non-specific grease 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.12-8.19 (m, 1 H),8.10 (br d, J = 7.79 Hz, 1 H), 7.82 (br d, J = 7.66 Hz, 1 H), 7.65 -7.75(m, 1 H), 7.45-7.51 (m, 1 H), 7.42 (br d, J = 7.79 Hz, 2 H), 7.35 (br d,J = 10.25 Hz, 1 H), 5.66- 5.98 (m, 1 H), 4.85 (t, J = 7.59 Hz, 1 H),4.57 (br t, J = 7.98 Hz, 1 H), 3.53- 3.70 (m, 2 H), 3.12 (s, 3 H),2.63-2.78 (m, 1 H), 2.43-2.54 (m, 1 H), 2.31 (dt, J = 13.56, 8.34 Hz, 1H), 1.02-1.17 (m, 1 H), 0.59- 0.66 (m, 1 H), 0.51-0.58 (m, 1 H),0.34-0.48 (m, 2 H) C 355

LCMS-ESI (POS.) m/z: 535.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.51- 8.93 (m, 2H), 7.56-8.08 (m, 6H), 3.88-5.31 (m, 5H), 3.35-3.42 (m,1H), 3.17- 3.29 (m, 1H), 2.56-2.65 (m, 4H), 2.06-2.28 (m, 1H), 1.26-1.78(m, 5H) L (2R)-1-((3-((trans-3-cyanocyclobutyl)sulfonyl)phenyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-2- piperidinecarboxamide 356

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3,5-trifluorobenzyl)-D- prolinamide LCMS-ESI(POS.) m/z: 514.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.34- 8.74(m, 1 H), 7.34-7.47 (m, 1 H), 6.91-7.04 (m, 1 H), 4.25-4.55 (m, 3 H),3.99-4.11 (m, 2 H), 3.86- 3.98 (m, 2 H), 3.74-3.83 (m, 1 H), 3.40-3.72(m, 4 H), 2.75-2.87 (m, 2 H), 2.61-2.71 (m, 1 H), 2.11 (dq, J = 12.25,8.11 Hz, 1 H), 1.87-2.33 (m, 3 H), 1.69-1.85 (m, 2 H), 1.35- 1.57 (m, 2H) A 357

(2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(4,6-difluoro-2,3-dihydrobenzofuran-3-yl)pyrrolidine-2- carboxamide LCMS-ESI (POS.)m/z: 524.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.38- 8.97 (m, 1 H),6.61-6.82 (m, 2 H), 5.51-5.70 (m, 1 H), 4.69-4.86 (m, 1 H), 4.16-4.45(m, 2 H), 4.00- 4.12 (m, 2 H), 3.87-3.99 (m, 2 H), 3.73-3.84 (m, 1 H),3.41-3.66 (m, 4 H), 2.59-2.89 (m, 3 H), 2.01- 2.30 (m, 1 H), 1.64-1.99(m, 5 H), 1.30-1.58 (m, 2 H) A 358

LCMS-ESI (POS.) m/z: 542.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.28- 8.75 (m, 1 H), 7.30-7.51 (m, 3 H), 4.27-4.52 (m, 3 H), 4.08 (br d,J = 2.08 Hz, 2 H), 3.91-3.96 (m, 2 H), 3.73-3.81 (m, 1 H), 3.29- 3.68(m, 4 H), 2.73-2.89 (m, 2 H), 2.61-2.73 (m, 1 H), 2.31-2.42 (m, 3 H),1.64-2.17 (m, 6 H), 1.31- 1.57 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-methyl-5-(trifluoromethyl)benzyl)-D-prolinamide 359

(2R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-sulfamoylbenzoyl)-2-piperidinecarboxamide LCMS-ESI (NEG.) m/z: 526.2 (M+31 H)⁻ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.91-8.08 (m, 2 H), 7.55-7.68 (m, 2 H), 7.45-7.53 (m, 1 H), 7.39-7.45 (m, 1 H), 7.35 (d, J =10.47 Hz, 1 H), 7.01-7.17 (m, 1 H), 4.63-5.30 (m, 3 H), 4.35- 4.62 (m, 1H), 3.53-3.68 (m, 1 H), 3.13-3.31 (m, 1 H), 2.17-2.33 (m, 1 H),1.64-1.91 (m, 4 H), 1.42- 1.59 (m, 1 H), 1.19-1.37 (m, 1 H), 0.52-0.76(m, 2 H), 0.34-0.49 (m, 2 H) C 360

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,4-difluorobenzyl)-D- prolinamide LCMS-ESI(POS.) m/z: 496.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.25- 8.66(m, 1 H), 7.26-7.37 (m, 1 H), 7.14-7.24 (m, 1 H), 7.04 (td, J = 8.30,2.98 Hz, 1 H), 4.17-4.54 (m, 3 H), 4.00-4.11 (m, 2 H), 3.88-3.97 (m, 2H), 3.79 (tq, J = 8.81, 5.94 Hz, 1 H), 3.34-3.68 (m, 4 H), 2.71- 2.87(m, 2 H), 1.85-2.32 (m, 4 H), 1.31-1.84 (m, 5 H) A 361

(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-2-azabicyc1o[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 534.1 (M +H)⁺ 1H NMR (DMSO-d6) δ: 9.20-9.14 (m, 2H), 8.78 (d, J = 7.4 Hz, 1H),8.42- 8.35 (m, 1H), 7.81 (dd, J = 9.5, 5.8 Hz, 1H), 7.63 (dd, J = 11.0,5.6 Hz, 1H), 4.99 (dd, J = 11.4, 3.6 Hz, 1H), 4.56 (t, J = 7.9 Hz, 1H),1.88-1.69 (m, 3H), 1.33- 1.18 (m, 2H), 1.18-1.10 (m, 1H), 0.88-0.74 (m,2H), 0.68-0.58 (m, 1H), 0.58-0.48 (m, 1H), 0.41 (s, 1H) Q 362

N-((R)-(4-chloro-2,5- difluorophenyl)(cyclopropyl)methyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D- prolinamide LCMS-ESI (POS.)m/z: 498.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 9.11- 9.22 (m, 1 H),8.79-9.09 (m, 1 H), 8.46-8.65 (m, 1 H), 8.26-8.46 (m, 1 H), 7.31-7.63(m, 2 H), 4.29 (s, 2 H), 3.51-3.61 (m, 2 H), 3.33-3.36 (m, 3 H),2.14-2.31 (m, 1 H), 1.65- 1.90 (m, 3 H), 0.84-1.24 (m, 1 H), −0.18-0.62(m, 4 H) C 363

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-methyl-N-(4- LCMS-ESI (POS.) m/z: 542.2 (M + H)⁺1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58-7.69 (m, 3 H), 7.46 (d, J =7.88 Hz, 1 H), 7.35 (d, J = 7.78 Hz, 2 H), 4.87 (dd, J = 7.88, 4.56 Hz,1 H), 4.68-4.78 (m, 2 H), 4.53- 4.66 (m, 1 H), 4.05-4.15 (m, 6 H),3.63-3.86 (m, 6 H), 3.38-3.49 (m, 1 H), 2.88-3.13 (m, 6 H), 2.69- 2.83(m, 3 H), 2.18-2.30 (m, 2 H), 1.91-2.16 (m, 5 H), 1.77-1.88 (m, 2 H),1.55-1.74 (m, 3 H) M (trifluoromethyl)benzyl)-D-prolinamide 364

LCMS-ESI (POS.) m/z: 513.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.49- 8.76 (m, 1 H), 7.51-8.10 (m, 7 H), 4.17-4.67 (m, 2 H), 3.35-3.64(m, 3 H), 3.24-3.30 (m, 3 H), 2.13- 2.31 (m, 1 H), 1.62-1.94 (m, 3 H),0.86-1.31 (m, 1 H), −0.06-0.65 (m, 4 H) C(R)-N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2- carboxamide 365

(4S)-N-((R)-(4-chloro-3-fluorophenyl)(3- oxetanyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide LCMS- APCI (POS.) m/z: 513.1 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.13 (t, J = 1.7 Hz, 1 H), 8.01(ddd, J = 1.1, 1.9, 7.9 Hz, 1 H), 7.86 (dt, J = 1.4, 7.7 Hz, 1 H), 7.67(t, J = 7.8 Hz, 1 H), 7.36 (t, J = 7.9 Hz, 1 H), 7.13 (dd, J = 2.0, 10.1Hz, 1 H), 7.05 (dd, J = 2.0, 8.2 Hz, 1 H), 5.30 (d, J = 10.4 Hz, 1 H),5.07- 5.24 (m, 1 H), 4.62 (dt, J = 6.7, 8.7 Hz, 1 H), 4.51- 4.58 (m, 2H), 4.33 (t, J = 6.2 Hz, 1 H), 3.93 (dt, J = 2.9, 12.5 Hz, 1 H), 3.59(ddd, J = 2.3, 12.7, 19.9 Hz, 1 H), 3.34-3.43 (m, 1 H), 3.25 (s, 2 H),3.07 (s, 3 H), 2.42-2.53 (m, 1 H), 1.93-2.11 (m, 1 H). A 366

(1R,3R,5R)-2-(3-cyanobenzoyl)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 488.2 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.06- 8.12 (m, 2 H), 7.89 (dt, 1H), 7.70 (td, J = 0.7, 7.8 Hz, 1 H), 7.48-7.58 (m, 3 H), 5.65 (d, J =10.2 Hz, 1 H), 4.99 (dd, J = 4.1, 11.4 Hz, 1 H), 4.83-4.87 (m, 1 H),4.60-4.70 (m, 2 H), 4.40 (t, 1 H), 3.51-3.61 (m, 1 H), 3.37 (s, 2 H),3.30 (td, J = 3.1, 6.2 Hz, 1 H), 2.60-2.71 (m, 1 H), 1.90 (dd, J = 4.1,13.5 Hz, 1 H), 1.74-1.83 (m, 1 H), 1.23 (td, J = 2.6, 5.3 Hz, 1 H), 0.88(ddd, J = 5.4, 7.3, 8.8 Hz, 1 H). Q 367

1-(((3S)-1-((3-(1H-pyrrol-1-)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 568.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (d, J = 8.04 Hz, 2 H),7.34-7.49 (m, 3 H), 6.87 (t, J = 1.95 Hz, 2 H), 6.22 (t, J = 1.95 Hz, 2H), 4.82 (quin, J = 7.07 Hz, 1 H), 4.60 (dd, J = 8.04, 1.56 Hz, 1 H),4.39-4.54 (m, 2 H), 4.21-4.28 (m, 2 H), 4.10- 4.19 (m, 2 H), 3.83 (br d,J = 12.46 Hz, 2 H), 3.55- 3.63 (m, 2 H), 2.92-2.99 (m, 1 H), 2.69-2.82(m, 2 H), 2.44 (ddd, J = 9.28, 6.42, 3.50 Hz, 1 H), 2.13-2.31 (m, 1 H),2.01-2.08 (m, 1 H), 1.76-1.95 (m, 3 H), 1.43-1.72 (m, 2 H), 1.19- 1.34(m, 2 H) M 368

N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(3-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)benzoyl)- D-prolinamide LCMS-ESI(POS.) m/z: 544.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 8.00 (s,1H), 7.94 (d, J = 7.88 Hz, 1H), 7.79 (br d, J = 7.77 Hz, 1H), 7.63-7.70(m, 1H), 7.49-7.56 (m, 1H), 7.40 (br d, J = 8.09 Hz, 1H), 7.29- 7.35 (m,2H), 4.75 (dd, J = 5.18, 7.05 Hz, 1H), 4.58 (br d, J = 5.91 Hz, 2H),3.57- 3.76 (m, 5H), 3.40-3.51 (m, 1H), 2.37-2.49 (m, 1H), 2.02-2.19 (m,3H), 1.86- 1.97 (m, 1H), 1.42-1.48 (m, 3H) C 369

LCMS-ESI (POS.) m/z: 475.2 (M + H)⁺ 1H NMR (600 MHz, DMSO-d6) δ ppm8.46- 8.80 (m, 1 H), 7.53-7.74 (m, 3 H), 6.96-7.40 (m, 4 H), 4.23-4.66(m, 2 H), 3.42-3.65 (m, 2 H), 2.08- 2.23 (m, 1 H), 1.15-2.05 (m, 5 H),0.06-1.09 (m, 9 H) C 1-(3-cyclopropylbenzoyl)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D- prolinamide 370

1-(3-(methylsulfonyl)benzoyl)-N-((R)-3- LCMS- APCI (POS.) m/z: 511.1(M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.20 (s, 1 H), 8.09 (d, J =7.9 Hz, 2 H), 7.94 (d, J = 7.7 Hz, 1 H), 7.75 (t, J = 7.7 Hz, 1 H), 7.67(d, J = 8.1 Hz, 2 H), 7.53 (d, J = 8.1 Hz, 2 H), 7.39 (d, 1 H), 5.48 (d,J = 10.2 Hz, 1 H), 4.88 (t, J = 7.1 Hz, 1 H), 4.47 (t, J = 6.2 Hz, 1H),3.97-4.17 (m, 1 H), 3.76 (s, 1 H), 3.60-3.69 (m, 1 H), 3.49-3.60 (m, 2H), 2.25-2.39 (m, 2 H), 1.78- 2.07 (m, 5 H). Aoxetanyl(4-(trifluoromethyl)phenyl)methyl)-D- prolinamide 371

1-(((3S)-1-((3-hydroxy-3-phenyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 595.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.52-7.66 (m, 4 H), 7.34- 7.45(m, 5 H), 4.47-4.64 (m, 2 H), 4.36-4.47 (m, 1 H), 4.10-4.30 (m, 4 H),3.81 (br t, J = 14.92 Hz, 2 H), 3.55-3.68 (m, 2 H), 2.94-3.14 (m, 2 H),2.80- 2.92 (m, 1 H), 2.74 (br t, J = 10.90 Hz, 1 H), 2.31- 2.45 (m, 1H), 2.12-2.31 (m, 1 H), 2.00-2.09 (m, 1 H), 1.86-1.98 (m, 2 H), 1.82 (brd, J = 13.49 Hz, 1 H), 1.67 (q, J = 12.46 Hz, 1 H), 1.42-1.61 (m, 1 H) M372

(1R,3R,5R)-2-(2-acetamidobenzoyl)-N-((R)- cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS- APCI (POS.) m/z: 504.1 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm9.58 (s, 1 H), 9.02 (d, J = 6.9 Hz, 1 H), 8.18 (d, J = 8.3 Hz, 1 H),7.60-7.72 (m, 2 H), 7.32-7.42 (m, 2 H), 7.15 (td, J = 1.1, 7.4 Hz, 1 H),4.98 (dd, J = 2.9, 11.4 Hz, 1 H), 4.46-4.54 (m, 1 H), 4.36 (t, J = 5.1Hz, 1 H), 3.40-3.46 (m, 1 H), 3.00 (td, J = 2.6, 6.2 Hz, 1 H), 2.56-2.65(m, 1 H), 1.94 (s, 2 H), 1.86 (dd, J = 3.0, 13.7 Hz, 1 H), 1.48-1.61 (m,1 H), 1.18-1.29 (m, 1 H), 1.06 (t, J = 7.0 Hz, 1 H), 0.57-0.67 (m, 2 H),0.46-0.57 (m, 2 H), 0.30- 0.46 (m, 2 H). Q 373

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((5-(trifluoromethyl)-2- LCMS-ESI (POS.) m/z:529.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 8.72- 8.88 (m, 1H),7.84-8.01 (m, 1H), 7.50-7.64 (m, 1H), 7.36-7.46 (m, 1H), 4.60- 4.75 (m,3H), 4.05-4.19 (m, 4H), 3.74-3.85 (m, 2H), 3.57-3.69 (m, 2H), 3.36- 3.50(m, 1H), 2.94-3.06 (m, 1H), 2.68-2.84 (m, 2H), 2.34-2.45 (m, 1H), 2.10-2.23 (m, 1H), 1.92-2.03 (m, 2H), 1.56-1.88 (m, 4H) Apyridinyl)methyl)-D-prolinamide 374

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 500.1 (M +H)⁺ 1H NMR (DMSO-d6) δ: 9.17-9.11 (m, 2H), 8.65 (d, J = 7.7 Hz, 1H),8.34 (s, 1H), 7.64 (dd, 1H), 7.50 (dd, J = 9.8, 6.4 Hz, 1H), 4.94 (dd, J= 11.4, 3.6 Hz, 2H), 4.50 (t, J = 7.9 Hz, 1H), 4.04 (q, J = 7.2 Hz, 2H),1.81-1.64 (m, 3H), 1.28-1.06 (m, 5H), 0.82- 0.67 (m, 2H), 0.59-0.49 (m,1H), 0.45 (t, J = 9.1 Hz, 2H), 0.38-0.27 (m, 2H) Q 375

(1R,3R,5R)-2-(3-(methylsulfonyl)benzoyl)-N-((R)-3-oxetanyl(4-(trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 523.1 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.40 (td, J = 0.5, 1.8 Hz, 1 H),8.13 (dddd, J = 1.1, 1.8, 4.1, 7.9 Hz, 2 H), 7.76- 7.81 (m, 1 H), 7.69(d, 2 H), 7.52 (d, 2 H), 5.41 (d, J = 10.1 Hz, 1 H), 5.02 (dd, J = 4.2,11.4 Hz, 1 H), 4.85 (dd, J = 6.5, 7.7 Hz, 1 H), 4.60-4.69 (m, 2 H), 4.44(t, J = 6.3 Hz, 1 H), 3.46- 3.55 (m, 1 H), 3.19 (s, 3 H), 2.63-2.72 (m,1 H), 1.92 (dd, J = 4.2, 13.5 Hz, 1 H), 1.76-1.85(m, 1 H), 1.29 (td, J =2.6, 5.3 Hz, 1 H), 0.87-0.95 (m, 1 H). A 376

LCMS- APCI (NEG.) m/z: 492.1 (M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm8.12 (d, J = 1.7 Hz, 1 H), 7.94- 8.03 (m, 2 H), 7.80 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 1.1 Hz, 1 H), 4.55 (t, J = 2.6 Hz, 3 H), 4.07-4.17 (m,2 H), 3.93 (dt, J = 5.8, 8.6 Hz, 2 H), 3.68 (dt, J = 6.9, 10.4 Hz, 1 H),3.45- 3.60 (m, 2 H), 2.28-2.40 (m, 1 H), 1.88-2.07 (m, 3 H). AN-((5-chloro-1,3-thiazol-2-yl)methyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D- prolinamide 377

(2R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2,3-dihydro-1H-pyrrole- 2-carboxamide LCMS-ESI(POS.) m/z: 511.0 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.16 (s,1H), 8.11 (br d, J = 7.79 Hz, 1H), 7.86 (d, J = 7.66 Hz, 1H), 7.69-7.77(m, 2H), 7.48-7.54 (m, 1H), 7.43 (d, J = 8.04 Hz, 1H), 7.36 (d, J =10.38 Hz, 1H), 6.31-6.37 (m, 1H), 5.33- 5.39 (m, 1H), 5.10 (dd, J =3.70, 10.45 Hz, 1H), 4.61 (t, J = 7.98 Hz, 1H), 3.21 (br dd, J = 1.43,17.26 Hz, 1H), 3.10-3.14 (m, 3H), 2.76- 2.98 (m, 1H), 1.26-1.35 (m, 1H),0.61-0.69 (m, 1H), 0.54-0.61 (m, 1H), 0.44- 0.50 (m, 1H), 0.37-0.44 (m,1H) K 378

LCMS-ESI (POS.) m/z: 469.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.52- 8.72 (m, 1 H), 7.27-7.74 (m, 7 H), 4.23-4.64 (m, 2 H), 3.50-3.62(m, 1 H), 3.45-3.49 (m, 1 H), 2.13- 2.22 (m, 1 H), 1.66-1.92 (m, 3 H),0.96-1.29 (m, 1 H), 0.03-0.64 (m, 4 H) C1-(3-chlorobenzoyl)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide 379

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-5-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 546.2 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.38- 8.80 (m, 1 H), 7.46-7.56 (m, 2H), 7.41 (br d, J = 9.73 Hz, 1 H), 4.32-4.55 (m, 2 H), 4.28 (dd, J =8.50, 4.22 Hz, 1 H), 3.99-4.09 (m, 2 H), 3.87-3.96 (m, 2 H), 3.75-3.83(m, 1 H), 3.61- 3.71 (m, 1 H), 3.33-3.61 (m, 3 H), 2.73-2.85 (m, 2 H),2.62-2.69 (m, 1 H), 2.06-2.28 (m, 1 H), 1.63- 1.97 (m, 5 H), 1.35-1.57(m, 2 H) A 380

1-(((3S)-1-((3-(trifluoromethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 571.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (m, J = 8.04 Hz, 2 H),7.41 (br s, 1 H), 7.28-7.37 (m, 2 H), 4.47-4.66 (m, 2 H), 4.37-4.47 (m,1 H), 4.22 (quin, J = 7.01 Hz, 1 H), 3.75-3.85 (m, 6 H), 3.56-3.65 (m, 2H), 2.89 (t, J = 11.81 Hz, 1 H), 2.67- 2.78 (m, 2 H), 2.57 (ddd, J =10.06, 6.94, 2.98 Hz, 2 H), 2.38-2.46 (m, 1 H), 2.02-2.24 (m, 4 H),1.85- 1.98 (m, 2 H), 1.78 (br d, J = 13.75 Hz, 1 H), 1.57- 1.70 (m, 1H), 1.36-1.57 (m, 2 H) M 381

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-2- methylbenzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 492.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.10- 8.50 (m, 1 H), 7.16-7.24 (m, 1 H), 6.99-7.05 (m, 1 H), 6.91-6.99(m, 1 H), 4.11-4.49 (m, 3 H), 4.01- 4.10 (m, 2 H), 3.88-3.97 (m, 2 H),3.74-3.84 (m, 1 H), 3.37-3.68 (m, 4 H), 2.71-2.87 (m, 2 H), 2.59- 2.69(m, 1 H), 2.16-2.33 (m, 3 H), 1.66-2.13 (m, 6 H), 1.32-1.56 (m, 2 H) A382

(1R,3R,5R)-2-(3-(ethylsulfonyl)benzoyl)-N-((S)-(2-fluoro-4-(trifluoromethyl)phenyl)(1- hydroxycyclopropyl)methyl)-2-LCMS-ESI (POS.) m/z: 555.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.61(br d, J = 8.04 Hz, 1 H) 8.10- 8.14 (m, 1 H) 8.02 (dd, J = 7.72, 1.62Hz, 2 H) 7.79 (t, J = 7.79 Hz, 1 H) 7.51- 7.75 (m, 4 H) 5.27-5.55 (m, 1H) 5.00 (dd, J = 11.35, 3.57 Hz, 1 H) 4.96 (d, J = 7.91 Hz, 1 H)3.32-3.38 (m, 2 H) 3.23 (td, J = 6.16, 2.47 Hz, 1 H) 1.07-1.16 (m, 5 H)0.52-0.78 (m, 6 H) C azabicyclo[3.1.0]hexane-3-carboxamide 383

LCMS- APCI (POS.) m/z: 505.2 (M + H)⁺ 1H NMR (400 MHz, MethyleneChloride-d2) δ ppm 8.07 (s, 1 H), 7.43- 7.56 (m, 2 H), 7.38 (d, J = 10.8Hz, 2 H), 7.17 (s, 1 H), 5.09 (dd, J = 10.4 Hz, 1 H), 4.58 (t, J = 8.0Hz, 1 H), 3.19-3.35 (m, 3 H), 2.49 (s, 3 H), 2.29-2.40 (m, 1 H),1.67-1.75 (m, 1 H), 1.39-1.56 (m, 3 H), 1.30 (t, J = 7.1 Hz, 3 H),1.17-1.27 (m, 2 H), 0.92- 1.00 (m, 1 H), 0.77-0.84 (m, 1 H), 0.51-0.66(m, 2 H), 0.36-0.46 (m, 2 H). S(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(ethylamino)-2-methyl-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 384

N-(4-(trifluoromethyl)benzyl)-1-(((3S)-1-(((3S)-3-(trifluoromethyl)-1-pyrrolidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide LCMS-ESI (POS.) m/z: 585.2 (M + H)⁺1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (d, J = 8.04 Hz, 2 H), 7.42(br s, 1 H), 7.35 (d, J = 7.50 Hz, 2 H), 4.57- 4.67 (m, 1 H), 4.53 (dd,J = 15.31, 6.49 Hz, 1 H), 4.41 (dd, J = 15.31, 5.71 Hz, 1 H), 3.72-3.89(m, 2 H), 3.52-3.66 (m, 3 H), 3.33- 3.45 (m, 3 H), 2.87-3.09 (m, 2 H),2.62-2.84 (m, 3 H), 2.44 (ddd, J = 9.34, 6.36, 3.50 Hz, 1 H), 2.01-2.24(m, 4 H), 1.85-1.98 (m, 2 H), 1.76-1.83 (m, 1 H), 1.62-1.75 (m, 1 H),1.39- 1.60 (m, 1 H) M 385

LCMS-ESI (POS.) m/z: 562.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ7.33- 8.07 (m, 8H), 7.16-7.26 (m, 1H), 4.54-4.78 (m, 2H), 4.06-4.20 (m,2H), 3.72- 3.77 (m, 2H), 3.57-3.69 (m, 3H), 3.47-3.55 (m, 1H), 2.38-2.50(m, 1H), 2.12- 2.26 (m, 2H), 1.58-1.99 (m, 1H), 1.43-1.53 (m, 3H) C1-(3-((3-hydroxy-3-methyl-1- azetidinyl)sulfonyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 386

LCMS-ESI (POS.) m/z: 551.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.48(s, 1 H), 7.20-8.02 (m, 8 H), 4.74-5.06 (m, 2 H), 4.25- 4.67 (m, 1 H),3.78-4.10 (m, 4 H), 3.43-3.71 (m, 5 H), 2.16-2.31 (m, 1 H), 1.73-2.01(m, 3 H) A 1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-2-hydroxy-1-(3- (trifluoromethyl)phenyl)ethyl)-D-prolinamide 387

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-methoxy-4- methylbenzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 504.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.18- 8.60 (m, 1 H), 7.00-7.12 (m, 1 H), 6.77-6.88 (m, 1 H), 6.66-6.75(m, 1 H), 4.19-4.50 (m, 3 H), 3.99- 4.13 (m, 2 H), 3.85-3.98 (m, 2 H),3.71-3.84 (m, 4 H), 3.46-3.69 (m, 4 H), 2.60-2.83 (m, 3 H), 2.02- 2.38(m, 4 H), 1.66-2.01 (m, 5 H), 1.31-1.56 (m, 2 H) A 388

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-2-methoxy-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide, 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- LCMS-ESI (POS.) m/z: 572.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.23- 8.81 (m, 1 H), 7.49-7.82(m, 4 H), 5.00-5.22 (m, 1 H), 4.32-4.59 (m, 1 H), 4.06 (br t, J = 8.24Hz, 2 H), 3.88-3.99 (m, 2 H), 3.74- 3.86 (m, 1 H), 3.47-3.67 (m, 6 H),3.21-3.27 (m, 3 H), 2.59-2.90 (m, 3 H), 2.02-2.34 (m, 1 H), 1.62- 2.00(m, 5 H), 1.30-1.57 (m, 2 H) Apiperidinyl)carbonyl)-N-((1S)-2-methoxy-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide 389

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((2-(ethylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 524.1 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.83- 8.99 (m, 1 H), 8.39-8.74 (m, 1H), 8.17 (s, 1 H), 7.95 (dd, J = 4.80, 1.43 Hz, 1 H),7.31-7.79 (m, 2 H),4.56-5.03 (m, 2 H), 4.02- 4.54 (m, 2 H), 3.76 (td, J = 6.23, 2.34 Hz, 1H), 3.40- 3.54 (m, 2 H), 3.29 (td, J = 6.16, 2.47 Hz, 1 H), 2.53- 2.77(m, 1 H), 1.54-1.81 (m, 2 H), 1.05-1.31 (m, 5 H), 0.41-0.99 (m, 3 H), −0.25-0.40 (m, 3 H) H 390

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,5-dichlorobenzyl)-D- prolinamide LCMS-ESI(POS.) m/z: 528.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.54 (brt, J = 5.86 Hz, 1 H), 7.25 (t, J = 1.87 Hz, 1 H), 7.11 (d, J = 1.87 Hz,2 H), 4.63 (dd, J = 7.98, 2.07 Hz, 1 H), 4.52 (dd, J = 15.65, 7.05 Hz, 1H), 4.23 (dd, J = 15.65, 5.18 Hz, 1 H), 4.06-4.16 (m, 4 H), 3.73- 3.82(m, 2 H), 3.54-3.64 (m, 2 H), 3.43 (tt, J = 8.68, 6.56 Hz, 1 H), 2.99(dd, J = 12.75, 10.99 Hz, 1 H), 2.66-2.83 (m, 2 H), 2.48 (ddt, J =12.44, 6.63, 2.75, 2.75 Hz, 1 H), 2.13-2.27 (m, 1 H), 2.01-2.12 (m, 1H), 1.98 (br d, J = 12.96 Hz, 1 H), 1.79-1.94 (m, 2 H), 1.62-1.74 (m, 1H), 1.51- 1.61 (m, 1 H) A 391

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(3,5-difluorophenyl)ethyl)-D-prolinamide LCMS-ESI (POS.) m/z: 510.2 (M + H)⁺1H NMR (500 MHz, DMSO-d6) δ ppm 8.16- 8.65 (m, 1 H), 6.94-7.18 (m, 3 H),4.84-4.98 (m, 1 H), 4.24-4.51 (m, 1 H), 4.01-4.09 (m, 2 H), 3.88- 3.97(m, 2 H), 3.74-3.85 (m, 1 H), 3.52-3.65 (m, 3 H), 3.32-3.51 (m, 1 H),2.65-2.86 (m, 2 H), 2.19- 2.35 (m, 1 H), 2.04-2.15 (m, 1 H), 1.62-1.96(m, 5 H), 1.38-1.56 (m, 2 H), 1.08-1.36 (m, 3 H) A 392

(1R,3R,5R)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 532.1 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (d, 1 H), 8.63 (d, J = 8.0,125.8 Hz, 1 H), 7.85-8.04 (m, 2 H), 7.58-7.74 (m, 3 H), 7.37-7.58 (m, 1H), 5.49 (t, 2 H), 4.90 (dd, J = 3.6, 11.3 Hz, 1 H), 4.65 (dd, J = 6.3,7.7 Hz, 1 H), 4.52 (dd, J = 6.2, 7.9 Hz, 1 H), 4.41 (t, J = 6.1 Hz, 1H), 4.20- 4.38 (m, 1 H), 3.59-3.88 (m, 1 H), 3.37-3.47 (m, 1 H), 3.29(dd, J = 2.6, 6.2 Hz, 1 H), 2.56-2.76 (m, 1 H), 1.57-1.76 (m, 2 H), 1.14(td, J = 2.5, 5.1 Hz, 1 H), 0.66-0.80 (m, 1 H). Q 393

(1R,2R,5S)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-3-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamideLCMS-ESI (POS.) m/z: 510.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm8.74-8.89 (m, 1 H), 8.01- 8.14 (m, 1 H), 7.49-7.63 (m, 1 H), 7.10-7.22(m, 2 H), 7.06 (br d, J = 6.95 Hz, 1 H), 4.79-5.35 (m, 1 H), 4.21-4.52(m, 1 H), 3.82- 4.19 (m, 1 H), 3.39 (d, J = 10.26 Hz, 1 H), 3.21- 3.32(m, 3 H), 1.85 (td, J = 7.44, 4.09 Hz, 1 H), 1.66- 1.74 (m, 1 H),1.11-1.29 (m, 1 H), 0.87 (td, J = 7.67, 6.01 Hz, 1 H), 0.51-0.70 (m, 2H), 0.33-0.49 (m, 2 H), 0.19-0.33 (m, 1 H) C 394

LCMS-ESI (POS.) m/z: 496.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.28- 8.70 (m, 1 H), 7.17-7.28 (m, 1 H), 7.01-7.17 (m, 2 H), 4.19-4.56(m, 3 H), 4.00-4.11 (m, 2 H), 3.87- 3.98 (m, 2 H), 3.74-3.83 (m, 1 H),3.38-3.70 (m, 4 H), 2.68-2.91 (m, 2 H), 1.88-2.33 (m, 4 H), 1.33- 1.87(m, 5 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,5-difluorobenzyl)-D- prolinamide 395

(1R,3R,5R)-N-((1S,2S)-1-(4-chloro-2,5-difluorophenyl)-2-hydroxypropyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane- 3-carboxamideLCMS-ESI (POS.) m/z: 527.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.45(d, J = 8.43 Hz, 1 H) 8.13 (s, 1 H) 8.00-8.06 (m, 2 H) 7.80 (t, J = 7.79Hz, 1 H) 7.62 (dd, J = 9.41, 6.16 Hz, 1 H) 7.41 (dd, J = 9.99, 6.10 Hz,1 H) 5.09 (dd, J = 11.29, 3.50 Hz, 1 H) 4.93-4.99 (m, 2 H) 3.79-3.86 (m,1 H) 3.33-3.37 (m, 2 H) 3.25 (td, J = 6.07, 2.40 Hz, 1 H) 2.54-2.62 (m,1 H) 1.74-1.79 (m, 1 H) 1.65- 1.72 (m, 1 H) 1.07-1.13 (m, 7 H) 0.71-0.78(m, 1 H) C 396

N-(2-chlorobenzyl)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-D- prolinamide LCMS- APCI (NEG.)m/z: 485.1 (M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm 8.13 (q, J = 2.0Hz, 1 H), 7.99 (ddd, J = 1.6, 3.1, 8.2 Hz, 2 H), 7.79 (dd, J = 6.5, 9.1Hz, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 7.34-7.41 (m, 1 H), 7.17-7.33 (m, 3H), 4.64 (ddd, J = 2.4, 6.1, 8.4 Hz, 1 H), 4.53 (d, J = 2.3 Hz, 2 H),4.11 (td, J = 2.3, 8.8 Hz, 2 H), 3.92 (dtd, J = 2.5, 5.6, 8.2 Hz, 3 H),3.68 (dt, J = 7.0, 9.7 Hz, 1 H), 3.48-3.61 (m, 2 H), 2.28- 2.46 (m, 1H), 2.00-2.07 (m, 2 H), 1.83-1.95 (m, 1 H). A 397

(4R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-4-hydroxy-1-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-D- prolinamide LCMS- APCI(POS.) m/z: 504.1 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 9.01 (dd, J =4.9, 33.8 Hz, 1 H), 8.71 (dd, J = 7.6, 67.9 Hz, 1 H), 8.04 (dt, J = 1.2,32.3 Hz, 1 H), 7.91 (ddd, J = 1.1, 4.4, 61.1 Hz, 1 H), 7.74 (ddd, J =6.2, 9.4, 12.0 Hz, 1 H), 7.52-7.68 (m, 1 H), 5.28 (dd, J = 5.4, 83.6 Hz,1 H), 4.57-4.68 (m, 1 H), 4.41- 4.57 (m, 1 H), 4.16-4.40 (m, 1 H), 3.85(ddd, J = 5.9, 11.0, 103.4 Hz, 1 H), 3.37-3.46 (m, 1 H), 2.56 (ddd, J =5.9, 9.1, 14.7 Hz, 1 H), 1.77-1.87(m, 1 H), 1.35 (dq, J = 3.6, 4.5, 8.2Hz, 1 H), 0.58-0.75 (m, 1 H), 0.52 (s, 1 H), 0.40- 0.49 (m, 1 H). Q 398

1-(((3S)-1-((3-(3-chlorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 613.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (d, J = 8.04 Hz, 2 H),7.43 (t, J = 6.76 Hz, 1 H), 7.24-7.36 (m, 5 H), 4.60 (br d, J = 6.49 Hz,1 H), 4.39- 4.55 (m, 3 H), 4.17-4.23 (m, 3 H), 3.97 (t, J = 7.40 Hz, 3H), 3.84 (br d, J = 12.20 Hz, 3 H), 3.75 (quin, J = 7.72 Hz, 1 H),3.56-3.65 (m, 3 H), 2.96 (t, J = 11.94 Hz, 1 H), 2.68- 2.84 (m, 3 H),2.44 (ddd, J = 9.21, 6.36, 3.37 Hz, 1 H), 2.14-2.31 (m, 1 H), 2.00- 2.09(m, 1 H), 1.85-1.95 (m, 3 H), 1.76-1.84 (m, 1 H), 1.61-1.74 (m, 1 H),1.53 (qd, J = 12.72, 3.63 Hz, 1H) M 399

(4R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-4-hydroxy-1-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-D- prolinamide LCMS- APCI (POS.)m/z: 520.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.88 (d, J = 4.9Hz, 1 H), 8.02 (s, 1 H), 7.84 (ddd, J = 1.5, 4.3, 6.3 Hz, 1 H), 7.35(ddd, J = 6.2, 9.5, 26.1 Hz, 2 H), 5.64 (dd, J = 5.2, 10.2 Hz, 1 H),4.70 (dd, J = 6.4, 7.8 Hz, 1 H), 4.58-4.66 (m, 2 H), 4.39-4.50 (m, 1 H),4.31-4.39 (m, 1 H), 3.68 (dd, J = 5.3, 10.6 Hz, 1 H), 3.52-3.59 (m, 1H), 3.47 (dd, J = 4.6, 10.5 Hz, 1 H), 2.43-2.59 (m, 1 H), 1.85-1.99 (m,1 H). Q 400

LCMS-ESI (POS.) m/z: 530.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.86- 8.98 (m, 2 H), 8.48-8.81 (m, 1 H), 4.33-4.58 (m, 2 H), 4.19-4.28(m, 1 H), 4.01-4.11 (m, 2 H), 3.88- 3.98 2 H), 3.74 3.83 (m, 1 H),3.31-3.70 (m, 4 H), 2.72-2.89 (m, 2 H), 2.58-2.70 (m, 1 H), 1.62- 2.40(m, 6 H), 1.33-1.56 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((2-(trifluoromethyl)-5-pyrimidinyl)methyl)-D-prolinamide 401

(2R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2,5-dihydro-1H-pyrrole- 2-carboxamide LCMS-ESI(POS.) m/z: 511.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm8.12-8.24 (m, 1 H), 7.96- 8.12 (m, 1 H), 7.76-7.91 (m, 1 H), 7.67-7.76(m, 1 H), 7.40-7.61 (m, 3 H), 7.32-7.39 (m, 1 H), 5.89- 6.18 (m, 2 H),5.44-5.61 (m, 1 H), 4.54-4.66 (m, 1 H), 4.34-4.53 (m, 1 H), 4.05-4.19(m, 1 H), 3.06- 3.17 (m, 3 H), 1.07-1.36 (m, 1 H), 0.59-0.73 (m, 1 H),0.52-0.59 (m, 1 H), 0.11-0.50 (m, 2 H) C 402

LCMS-ESI (POS.) m/z: 531.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.55- 8.94 (m, 1 H), 7.44-8.13 (m, 7 H), 5.16-5.46 (m, 1 H), 4.56-4.80(m, 2 H), 3.48-4.15 (m, 3 H), 3.26- 3.31 (m, 3 H), 1.81-2.05 (m, 1 H),0.80-1.27 (m, 1 H),-0.28-0.68 (m, 4 H) C(2R,4S)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)pyrrolidine-2- carboxamide 403

(1R,3R,5R)-N-((R)-(4-chlorophenyl)(3-oxetanyl)methyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 503.1 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.35 (t, J = 1.7 Hz, 1 H), 8.13(dt, J = 1.3, 7.7 Hz, 1 H), 8.07 (ddd, J = 1.1, 1.9, 7.9 Hz, 1 H), 7.79(t, J = 7.8 Hz, 1 H), 7.35-7.41 (m, 2 H), 7.28-7.34 (m, 2 H), 5.33 (d, J= 10.2 Hz, 1 H), 4.99 (dd, J = 4.2, 11.4 Hz, 1 H), 4.83 (dd, J = 6.4,7.7 Hz, 1 H), 4.58-4.67 (m, 2 H), 4.40 (t, J = 6.3 Hz, 1 H), 3.42-3.52(m, 1 H), 3.23-3.38 (m, 7 H), 2.66 (dddd, J = 1.1, 6.5, 11.4, 12.4 Hz, 1H), 1.91 (dd, 1 H), 1.75-1.84 (m, 1 H), 1.23-1.31 (m, 4 H), 0.90 (dtd, J= 1.1, 5.6, 9.0 Hz, 1 H). A 404

LCMS-ESI (POS.) m/z: 558.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.13- 8.81 (m, 1 H), 7.46-7.70 (m, 4 H), 4.82-5.00 (m, 2 H), 4.32-4.60(m, 1 H), 4.01-4.15 (m, 2 H), 3.89- 4.00 (m, 2 H), 3.75-3.85 (m, 1 H),3.46-3.70 (m, 5 H), 3.35-3.42 (m, 1 H), 2.70-2.89 (m, 2 H), 2.62- 2.70(m, 1 H), 2.07-2.39 (m, 1 H), 1.60-1.98 (m, 5 H), 1.31-1.58 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-2-hydroxy-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide 405

LCMS-ESI (POS.) m/z: 513.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.21- 8.49 (m, 1 H) 7.19-8.20 (m, 6 H) 4.64-5.12 (m, 3 H) 3.68-3.88 (m,1 H) 3.22-3.28 (m, 4 H) 2.57 (td, J = 12.52, 6.23 Hz, 1 H) 1.53-1.81 (m,2 H) 0.41- 1.16 (m, 5 H) A (1R,3R,5R)-N-((1S,2S)-1-(4-chloro-2,5-difluorophenyl)-2-hydroxypropyl)-2-(3- (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 406

LCMS-ESI (POS.) m/z: 512.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.23- 8.79 (m, 1 H), 7.09-7.55 (m, 3 H), 4.21-4.51 (m, 3 H), 3.99-4.14(m, 2 H), 3.88-3.99 (m, 2 H), 3.73- 3.85 (m, 1 H), 3.34-3.69 (m, 4 H),2.71-2.88 (m, 2 H), 2.61-2.71 (m, 1 H), 1.63-2.30 (m, 6 H), 1.32- 1.55(m, 2 H) A N-(3-chloro-2-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 407

(1R,2R,5S)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-(3- (methylsulfonyl)benzoyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide LCMS-ESI (POS.) m/z: 525.0 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.97-8.10 (m, 2 H), 7.72- 7.80(m, 1 H), 7.65-7.72 (m, 1 H), 7.46-7.53 (m, 1 H), 7.39-7.46 (m, 1 H),7.30-7.39 (m, 1 H), 7.22- 7.27 (m, 1 H), 4.85-4.97 (m, 1 H), 4.53-4.65(m, 1 H), 3.87 (dd, J = 10.31, 4.09 Hz, 1 H), 3.45 (d, J = 10.37 Hz, 1H), 3.10 (s, 2 H), 3.00-3.13 (m, 1 H), 1.83- 1.91 (m, 1 H), 1.62-1.71(m, 1 H), 1.21-1.34 (m, 1 H), 0.78-0.89 (m, 1 H), 0.50-0.69 (m, 2 H),0.29- 0.49 (m, 2 H), 0.19-0.27 (m, 1 H) C 408

LCMS-ESI (POS.) m/z: 508.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.56(br d, J = 8.04 Hz, 1 H), 6.65- 7.92 (m, 7 H), 4.01-4.58 (m, 2 H),3.43-3.72 (m, 2 H), 2.63 (s, 6 H), 2.25 (br s, 1 H), 1.71-2.01 (m, 3 H),1.00-1.14 (m, 1 H), 0.18- 0.62 (m, 4 H) A N-((S)-(4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide 409

(1R,3R,5R)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((4-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 532.1 (M +H)⁺ 1H NMR (Methanol-d4) δ: 8.93 (d, J = 5.1 Hz, 1H), 8.74 (d, J = 5.1Hz, 1H), 8.23-8.13 (m, 2H), 7.85 (d, J = 5.1 Hz, 1H), 7.77 (d, J = 5.1Hz, 1H), 7.62-7.36 (m, 5H), 5.72 (dd, J = 11.7, 3.0 Hz, 1H), 5.67 (d, J= 10.2 Hz, 1H), 5.32 (d, J = 9.6 Hz, 1H), 5.00 (dd, J = 11.5, 3.8 Hz,1H), 4.72- 4.61 (m, 2H), 4.57-4.50 (m, 1H), 4.42 (t, J = 6.2 Hz, 1H),4.16 (t, J = 6.1 Hz, 1H), 4.04 (t, J = 6.3 Hz, 1H), 3.97 (td, J = 6.3,2.6 Hz, 1H), 3.57 (d, J = 15.6 Hz, 1H), 2.90-2.77 (m, 1H), 2.72-2.58 (m,1H), 1.99 (dd, J = 13.4, 3.0 Hz, 1H), 1.92 (dd, J = 13.5, 3.8 Hz, 1H),1.82-1.72 (m, 1H), 1.71-1.60 (m, 1H), 1.31 (s, 3H), 1.18-1.11 (m, 1H),0.99-0.72 (m, 5H) Q 410

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-D-prolinamide LCMS-ESI (POS.) m/z: 529.2 (M + H)⁺ 1HNMR (500 MHz, DMSO-d6) δ ppm 8.78* (t, J = 5.77 Hz, 1 H), 8.62- 8.68 (m,1 H), 8.45 (t, J = 5.97 Hz, 1 H), 7.90 (t, J = 6.81 Hz, 1 H), 7.83- 7.88(m, 1 H), 4.24-4.52 (m, 3 H), 4.01-4.10 (m, 2 H), 3.90-3.97 (m, 2 H),3.79 (tq, J = 8.85, 6.00 Hz, 1 H), 3.31-3.69 (m, 4 H), 2.73-2.89 (m, 2H), 2.65 (tt, J = 11.14, 3.39 Hz, 1 H), 2.26-2.34* (m, 1 H), 2.17 -2.26*(m, 1 H), 2.07- 2.15 (m, 1 H), 1.66-1.99 (m, 5 H), 1.36-1.55 (m, 2 H).Spectrum appears as 3:1 mixture of rotamers, *denotes resolved minorrotamer peaks. C 411

LCMS-ESI (POS.) m/z: 530.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.38- 8.76 (m, 1 H), 7.72-8.04 (m, 4 H), 7.43-7.67 (m, 4 H), 5.21-5.47(m, 1 H), 4.56-5.09 (m, 2 H), 3.60- 4.07 (m, 7 H), 2.53-2.61 (m, 1 H),1.90-2.08 (m, 1 H), 0.96-1.48 (m, 3 H) C (4S)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-4-fluoro-N-((1R)-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide 412

(1R,3R,5R)-2-(3-(2-cyano-2-propanyl)benzoyl)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS- APCI(POS.) m/z: 530.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.00 (t,J = 1.8 Hz, 1 H), 7.75 (dt, J = 1.4, 7.6 Hz, 1 H), 7.71 (ddd, J = 1.1,2.1, 8.0 Hz, 1 H), 7.54-7.59 (m, 3 H), 7.49-7.54 (m, 1 H), 5.66 (d, J =10.1 Hz, 1 H), 5.00 (dd, J = 4.2, 11.4 Hz, 1 H), 4.83-4.86 (m, 1 H),4.62-4.70 (m, 2 H), 4.40 (t, J = 6.2 Hz, 1 H), 3.30 (dd, J = 2.7, 6.3Hz, 1 H), 2.60-2.70 (m, 1 H), 1.91 (dd, J = 4.2, 13.6 Hz, 1 H), 1.78 (s,8 H), 1.24 (td, J = 2.6, 5.3 Hz, 1 H), 0.89 (dt, J = 5.7, 8.6 Hz, 1 H).Q 413

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(fluoromethyl)benzyl)- D-prolinamide LCMS-ESI(POS.) m/z: 492.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 7.25-7.42 (m, 4 H), 5.40-5.44 (m, 1 H), 5.32- 5.35 (m, 1 H),4.25-4.50 (m, 3 H), 4.03-4.11 (m, 2 H), 3.90-3.97 (m, 2 H), 3.76-3.83(m, 1 H), 3.34- 3.69 (m, 4 H), 2.73-2.86 (m, 2 H), 2.61-2.70 (m, 1 H),2.03-2.23 (m, 1 H), 1.66-1.96 (m, 5 H), 1.34- 1.55 (m, 2 H) F 414

N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(3-(2-propanyl)benzoyl)-D-prolinamide LCMS-ESI (POS.) m/z: 477.2 (M + H)⁺ 1HNMR (500 MHz, CHLOROFORM-d) δ ppm 7.93 (br d, J = 6.75 Hz, 1 H),7.45-7.57 (m, 1 H), 7.29- 7.44 (m, 7 H), 4.83 (dd, J = 7.66, 4.80 Hz, 1H), 4.65 (t, J = 7.79 Hz, 1 H), 3.37- 3.61 (m, 2 H), 2.97 (dt, J =13.75, 6.88 Hz, 1 H), 2.41-2.54 (m, 1 H), 1.93- 2.19 (m, 2 H), 1.76-1.93(m, 1 H), 1.29 (d, J = 6.75 Hz, 7 H), 0.48-0.71 (m, 2 H), 0.33-0.48 (m,2 H) C 415

LCMS-ESI (POS.) m/z: 530.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.23- 8.56 (m, 1 H), 7.68 (d, J = 8.04 Hz, 2 H), 7.47- 7.57 (m, 2 H),4.85-5.04 (m, 2 H), 4.01-4.12 (m, 2 H), 3.90-3.99 (m, 2 H), 3.48-3.84(m, 3 H), 2.69- 2.97 (m, 6 H), 1.65-1.91 (m, 2 H), 1.33-1.61 (m, 6 H),1.23 (dd, J = 9.34, 7.27 Hz, 2 H) B(3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-(((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)-3- piperidinecarboxamide 416

(4S)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-((2- LCMS-ESI (POS.) m/z:550.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.67- 8.99 (m, 2 H),7.68-8.08 (m, 3 H), 7.37-7.60 (m, 1 H), 5.21-5.39 (m, 1 H), 4.52-4.68(m, 2 H), 3.84- 4.01 (m, 1 H), 3.55-3.71 (m, 1 H), 3.26-3.41 (m, 3 H),2.53-2.63 (m, 1 H), 1.90-2.11 (m, 1 H), 0.86- 1.31 (m, 1 H), − 0.26-0.69(m, 4 H) C (methylsulfonyl)-4-pyridinyl)carbonyl)-D- prolinamide 417

LCMS-ESI (POS.) m/z: 504.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.93- 8.43 (m, 1 H), 6.92-7.15 (m, 1 H), 6.62-6.89 (m, 2 H), 4.11-4.53(m, 3 H), 3.87-4.09 (m, 4 H), 3.71- 3.82 (m, 4 H), 3.42-3.70 (m, 4 H),2.61-2.90 (m, 3 H), 2.28 (s, 3 H), 1.68- 2.22 (m, 6 H), 1.33-1.56 (m, 1H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methoxy-4- methylbenzyl)-D-prolinamide 418

LCMS-ESI (POS.) m/z: 512.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.28- 8.76 (m, 1 H), 7.00-7.48 (m, 3 H), 4.24-4.38 (m, 3 H), 3.98-4.06(m, 1 H), 3.85-3.97 (m, 2 H), 3.71- 3.83 (m, 1 H), 3.31-3.67 (m, 4 H),2.72-2.86 (m, 2 H), 2.62-2.70 (m, 1 H), 2.06-2.28 (m, 1 H), 1.67- 1.98(m, 5 H), 1.30-1.52 (m, 2 H), 1.20-2.03 (m, 1 H) AN-(2-chloro-3-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 419

(2S)-N-((2R)-1-(((1R)-1-(4-chloro-2-fluorophenyl)ethyl)amino)-1-oxo-2-propanyl)-4-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-2- morpholinecarboxamideLCMS-ESI (POS.) m/z: 516.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.34- 8.53 (m, 1 H), 7.34-7.48 (m, 2 H), 7.25-7.31 (m, 1 H), 5.00-5.17(m, 1 H), 4.59-4.88 (m, 1 H), 4.26- 4.41 (m, 1 H), 4.08-4.18 (m, 2 H),3.97-4.07 (m, 2 H), 3.79-3.96 (m, 2 H), 3.57-3.75 (m, 1 H), 3.34- 3.54(m, 2 H), 3.04 (ddd, J = 16.84, 12.36, 9.99 Hz, 1 H), 2.64-2.99 (m, 4H), 1.29-1.39 (m, 3 H), 1.24 (dd, J = 17.19, 6.94 Hz, 3 H) C 420

LCMS-ESI (POS.) m/z: 501.0 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.21- 8.76 (m, 2H), 7.61-8.04 (m, 5H), 7.38-7.55 (m, 1H), 4.01-5.25 (m,4H), 3.34- 3.44 (m, 1H), 3.14-3.28 (m, 1H), 2.55-2.66 (m, 4H), 2.04-2.28(m, 1H), 1.20- 1.77 (m, 5H) L(2R)-N-((6-chloro-3-pyridinyl)methyl)-1-((3- ((trans-3-cyanocyclobutyl)sulfonyl)phenyl)carbonyl)-2- piperidinecarboxamide 421

N-((R)-(4-chloro-2,5- difluorophenyl)(cyclopropyl)methyl)-1-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-D- prolinamide LCMS-ESI (POS.)m/z: 498.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.83- 8.96 (m, 1 H),8.64 (br d, J = 7.66 Hz, 1 H), 7.76- 8.12 (m, 2 H), 7.39-7.69 (m, 2 H),4.09-4.55 (m, 2 H), 3.49-3.64 (m, 2 H), 3.32 (br d, J = 15.05 Hz, 3 H),2.10-2.32 (m, 1 H), 1.64-1.94 (m, 3 H), 0.86- 1.24 (m, 1 H), 0.37 (br s,4 H) C 422

LCMS- APCI (POS.) m/z: 598.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 8.80- 8.86 (m, 1 H), 8.27 (s, 1 H), 8.02 (s, 1 H), 7.81- 7.86 (m, 1H), 7.71-7.77 (m, 1 H), 7.58-7.70 (m, 2 H), 7.51-7.55 (m, 1 H),7.43-7.49 (m, 1 H), 4.30- 4.52 (m, 6 H), 3.06-3.12 (m, 3 H), 2.64-2.73(m, 1 H), 1.91-1.97 (m, 1 H), 1.75-1.81 (m, 1 H), 1.24- 1.35 (m, 2 H),1.15-1.19 (m, 1 H), 0.82-0.89 (m, 1 H), 0.64-0.73 (m, 1 H), 0.41-0.60(m, 3 H). W (1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(3-fluoro-1-(methylsulfonyl)-3-azetidinyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 423

LCMS-ESI (POS.) m/z: 532.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.21- 8.67 (m, 1 H), 7.36-7.55 (m, 1 H), 4.15-4.44 (m, 3 H), 4.01-4.08(m, 2 H), 3.86-3.97 (m, 2 H), 3.74- 3.83 (m, 1 H), 3.36-3.62 (m, 4 H),2.57-2.83 (m, 3 H), 1.81-2.25 (m, 4 H), 1.63-1.77 (m, 2 H), 1.32- 1.57(m, 2 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3,4,6- tetrafluorobenzyl)-D-prolinamide 424

1-(((3S)-1-((3-(4-chlorophenoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 629.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (d, J = 8.04 Hz, 2 H),7.44 (br s, 1 H), 7.28-7.40 (m, 2 H), 7.23-7.26 (m, 2 H), 6.64-6.70 (m,2 H), 4.83-4.90 (m, 1 H), 4.56- 4.68 (m, 1 H), 4.36-4.56 (m, 2 H),4.11-4.29 (m, 2 H), 4.00 (dt, J = 8.63, 4.12 Hz, 2 H), 3.81 (br d, J =12.72 Hz, 2 H), 3.52- 3.65 (m, 2 H), 2.89-2.99 (m, 1 H), 2.67-2.81 (m, 2H), 2.42-2.62 (m, 1 H), 2.11-2.33 (m, 2 H), 1.97- 2.09 (m, 1 H),1.59-1.94 (m, 5 H), 1.44-1.59 (m, 2 H) M 425

LCMS- APCI (POS.) m/z: 545.2 (M + H)⁺ 1H NMR (Methanol-d4) δ: 7.65 (dd,J = 18.5, 7.9 Hz, 2H), 7.50 (d, J = 7.8 Hz, 2H), 4.66-4.38 (m, 3H),3.94-3.68 (m, 4H), 3.69- 3.39 (m, 1H), 3.11 (p, J = 9.1 Hz, 1H), 2.91(q, J = 11.7, 11.0 Hz, 1H), 2.85- 2.75 (m, 2H), 2.62 (q, J = 10.1 Hz,2H), 2.54-2.41 (m, 2H), 2.41-2.21 (m, 1H), 2.16-1.89 (m, 4H), 1.89-1.77(m, 1H), 1.69- 1.50 (m, 2H) R1-(((3S)-1-((cis-3-carbamoylcyclobutyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 426

LCMS-ESI (POS.) m/z: 479.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.37- 8.60 (m, 1 H), 7.04-8.09 (m, 7 H), 3.82-4.56 (m, 2 H), 3.39-3.67(m, 2 H), 3.21-3.31 (m, 3 H), 2.15- 2.34 (m, 1 H), 1.68-1.93 (m, 3H),-0.19-1.23 (m, 5 H) C N-((R)-(4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 427

(4S)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-fluoro-N-(3- LCMS-ESI (POS.) m/z: 546.2 (M + H)⁺1H NMR (500 MHz, DMSO-d6) δ ppm 8.55- 8.87 (m, 1 H), 7.61-7.67 (m, 1 H),7.52-7.61 (m, 3 H), 5.23-5.49 (m, 1 H), 4.32-4.68 (m, 3 H), 4.02- 4.09 2H), 3.89 4.02 (m, 3 H), 3.70-3.88 (m, 2 H), 3.55 (br d, J = 11.55 Hz, 2H), 2.72-2.90 (m, 2 H), 2.61-2.72 (m, 1 H), 2.39- 2.47 (m, 1 H),1.94-2.21 (m, 1 H), 1.78-1.93 (m, 1 H), 1.72 (br d, J = 13.36 Hz, 1 H),1.45-1.57 (m, 1 H), 1.31-1.45 (m, 1 H) C(trifluoromethyl)benzyl)-D-prolinamide 428

1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-((1R)-1-(4- LCMS-ESI (POS.) m/z: 543.2 (M + Na)⁺1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.53-7.65 (m, 2 H), 7.28- 7.45 (m,3 H), 5.03 (t, J = 6.95 Hz, 1 H), 4.53 (br d, J = 6.84 Hz, 1 H), 4.03-4.25 (m, 4 H), 3.83 (br t, J = 7.46 Hz, 1 H), 3.66- 3.78 (m, 2 H),3.41-3.63 (m, 3 H), 3.15 (br d, J = 13.68 Hz, 1 H), 2.76- 2.99 (m, 3 H),1.77-2.47 (m, 5 H), 1.40 (s, 3 H) M(trifluoromethyl)phenyl)ethyl)-D-prolinamide 429

N-(3,5-difluorobenzyl)-1-(((3S)-1-((3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide LCMS-ESI (POS.) m/z: 549.0 (M + H)⁺1H NMR (400 MHz, CHLOROFORM-d) δ 7.40- 7.57 (m, 1H), 6.64-6.80 (m, 3H),4.62 (dd, J = 2.02, 8.03 Hz, 1H), 4.51 (dd, J = 6.89, 15.70 Hz, 1H),4.16-4.33 (m, 5H), 3.90-4.00 (m, 1H), 3.74-3.84 (m, 2H), 3.52- 3.64 (m,2H), 2.93-3.06 (m, 4H), 2.78-2.87 (m, 1H), 2.69-2.78 (m, 1H), 2.42- 2.51(m, 1H), 2.13-2.26 (m, 1H), 2.03-2.11 (m, 1H), 1.79-2.00 (m, 3H), 1.65-1.73 (m, 1H), 1.53-1.61 (m, 1H) A 430

(4S)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-((5- LCMS-ESI (POS.) m/z:550.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.65- 9.25 (m, 3 H),8.27-8.45 (m, 1 H), 7.65-7.81 (m, 1 H), 7.37-7.62 (m, 1 H), 5.29-5.46(m, 1 H), 4.49- 4.72 (m, 2 H), 3.60-4.09 (m, 2 H), 3.34-3.48 (m, 3 H),2.53-2.64 (m, 1 H), 1.86-2.09 (m, 1 H), 0.82- 1.30 (m, 1 H), −0.31-0.67(m, 4 H) C (methylsulfonyl)-3-pyridinyl)carbonyl)-D- prolinamide 431

LCMS-ESI (POS.) m/z: 542.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.22- 8.69 (m, 1 H), 7.62-7.77 (m, 2 H), 7.48-7.60 (m, 2 H), 4.86-5.04(m, 1 H), 4.28-4.45 (m, 1 H), 4.00- 4.09 (m, 2 H), 3.88-3.98 (m, 2 H),3.74-3.83 (m, 1 H), 3.46-3.64 (m, 4 H), 2.73-2.91 (m, 2 H), 2.57- 2.67(m, 1 H), 2.02-2.23 (m, 1 H), 1.67-1.95 (m, 5 H), 1.33-1.56 (m, 5 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide 432

LCMS-ESI (NEG.) m/z: 515.2 (M − H)⁻ 1H NMR (500 MHz, DMSO-d6) δ ppm8.30- 8.73 (m, 1 H), 7.68 (br t, J = 6.62 Hz, 2 H), 7.38- 7.51 (m, 2 H),4.62-5.02 (m, 1 H), 4.27-4.43 (m, 2 H), 3.46-4.11 (m, 6 H), 2.66-2.98(m, 6 H), 1.60- 1.90 (m, 2 H), 1.29-1.59 (m, 3 H), 1.14-1.29 (m, 3 H) C(3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-((4- (trifluoromethyl)benzyl)amino)ethyl)-3-piperidinecarboxamide 433

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3-dimethylbenzyl)-D- prolinamide LCMS-ESI(POS.) m/z: 487.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.04- 8.46(m, 1 H), 6.98-7.10 (m, 3 H), 4.14-4.49 (m, 3 H), 4.01-4.10 (m, 2 H),3.88-3.97 (m, 2 H), 3.74- 3.84 (m, 1 H), 3.34-3.68 (m, 4 H), 2.67-2.89(m, 2 H), 2.17-2.34 (m, 4 H), 2.09-2.15 (m, 3 H), 1.68- 2.10 (m, 6 H),1.31-1.54 (m, 2 H) A 434

1-((3-(5-azaspiro[2.3]hex-5- ylsulfonyl)phenyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide LCMS- APCI (NEG.) m/z:534.2 (M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm 8.12 (t, J = 1.8 Hz, 1H), 7.97 (ddt, J = 1.5, 7.8, 16.0 Hz, 2 H), 7.75-7.79 (m, 1 H), 7.63 (d,J = 8.1 Hz, 2 H), 7.52 (d, J = 8.1 Hz, 2 H), 4.98-5.16 (m, 1 H), 4.61(dd, J = 5.9, 8.2 Hz, 1 H), 3.88 (s, 4 H), 3.63 (dt, J = 7.0, 10.8 Hz, 1H), 3.46- 3.57 (m, 1 H), 2.27-2.39 (m, 1 H), 1.87-1.98 (m, 3 H), 1.53(d, J = 7.0 Hz, 3 H), 0.47 (s, 4 H). A 435

LCMS-ESI (POS.) m/z: 526.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.18- 8.68 (m, 1 H), 6.98-7.48 (m, 5 H), 4.19-4.50 (m, 3 H), 3.90-4.12(m, 4 H), 3.74-3.85 (m, 1 H), 3.44- 3.70 (m, 4 H), 2.62-2.90 (m, 3 H),1.67-2.34 (m, 6 H), 1.34-1.56 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(difluoromethoxy)benzyl)-D-prolinamide 436

1-(3-(dimethylsulfamoyl)benzoyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide LCMS-ESI (POS.) m/z: 498.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.26- 8.60 (m, 1 H), 7.78-7.91(m, 1 H), 7.71-7.93 (m, 1 H), 7.36-7.98 (m, 1 H), 4.66-5.06 (m, 1 H),4.25- 4.55 (m, 1 H), 3.41-3.65 (m, 2 H), 3.32 (s, 4 H), 2.71-2.72 (m, 1H), 2.57- 2.70 (m, 6 H), 2.15-2.31 (m, 1 H), 1.71-1.96 (m, 3 H),1.06-1.47 (m, 3 H) D 437

LCMS-ESI (POS.) m/z: 478.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.22- 8.66 (m, 1 H), 7.22-7.30 (m, 2 H), 7.08-7.18 (m, 2 H), 4.17-4.48(m, 3 H), 4.01-4.11 (m, 2 H), 3.88- 3.99 (m, 2 H), 3.74-3.83 (m, 1 H),3.34-3.70 (m, 4 H), 2.59-2.89 (m, 3 H), 2.03-2.32 (m, 1 H), 1.64- 1.98(m, 5 H), 1.34-1.56 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluorobenzyl)-D- prolinamide 438

N-(3-chlorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide LCMS-ESI(POS.) m/z: 494.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.24- 8.79(m, 1 H), 7.20-7.38 (m, 3 H), 7.15 (br d, J = 7.40 Hz, 1 H), 4.13-4.35(m, 3 H), 3.94-4.08 (m, 2 H), 3.81-3.93 (m, 2 H), 3.69- 3.80 (m, 1 H),3.22-3.64 (m, 4 H), 2.67-2.84 (m, 2 H), 2.51-2.66 (m, 1 H), 2.03-2.31(m, 1 H), 1.60- 1.96 (m, 5 H), 1.26-1.54 (m, 2 H) A 439

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-3- LCMS-ESI (POS.) m/z: 492.2 (M + H)⁺1H NMR (500 MHz, DMSO-d6) δ ppm 8.17- 8.61 (m, 1 H), 6.96-7.25 (m, 3 H),4.18-4.51 (m, 3 H), 4.00-4.11 (m, 2 H), 3.86-4.00 (m, 2 H), 3.72- 3.83(m, 1 H), 3.41-3.70 (m, 4 H), 2.60-2.90 (m, 3 H), 2.16-2.34 (m, 3 H),2.03-2.14 (m, 1 H), 1.65- 2.03 (m, 5 H), 1.32-1.59 (m, 2 H) Amethylbenzyl)-D-prolinamide 440

LCMS-ESI (POS.) m/z: 512.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.39(br t, J = 5.97 Hz, 1 H), 7.05 -7.59 (m, 3 H), 4.21-4.59 (m, 3 H),4.00-4.14 (m, 2 H), 3.85-4.00 (m, 2 H), 3.74-3.85 (m, 1 H), 3.37- 3.73(m, 4 H), 2.73-2.87 (m, 2 H), 2.61-2.71 (m, 1 H), 1.63-2.29 (m, 6 H),1.32-1.56 (m, 2 H) A N-(2-chloro-5-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 441

LCMS-ESI (POS.) m/z: 542.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.19(d, J = 8.17 Hz, 1 H), 7.07- 7.57 (m, 3 H), 5.23-5.24 (m, 1 H), 4.78 (brd, J = 7.66 Hz, 1 H), 4.39 (dd, J = 8.17, 3.50 Hz, 1 H), 3.70-4.11 (m, 5H), 3.30-3.63 (m, 6 H), 3.24-4.17 (m, 1 H), 2.57-2.88 (m, 3 H), 1.72-2.27 (m, 6 H), 1.32-1.58 (m, 2 H) AN-((1R)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 442

LCMS-ESI (POS.) m/z: 486.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.96- 8.58 (m, 1 H), 7.03-7.32 (m, 4 H), 5.20-5.40 (m, 1 H), 4.20-4.48(m, 1 H), 3.87-4.14 (m, 4 H), 3.42- 3.85 (m, 5 H), 2.60-2.97 (m, 5 H),1.67-2.44 (m, 8 H), 1.31-1.58 (m, 2 H) A(2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(2,3-dihydro-1H-inden-1-yl)pyrrolidine-2-carboxamide 443

LCMS-ESI (POS.) m/z: 508.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.23- 8.66 (m, 1 H), 6.94-7.19 (m, 3 H), 5.50-5.51 (m, 1 H), 4.14-4.54(m, 3 H), 3.99-4.09 (m, 2 H), 3.86- 3.97 (m, 2 H), 3.74-3.84 (m, 1 H),3.40-3.71 (m, 4 H), 3.32-3.39 (m, 1 H), 2.71-2.90 (m, 2 H), 2.60- 2.71(m, 1 H), 2.02-2.25 (m, 1 H), 1.63-1.99 (m, 5 H), 1.33-1.59 (m, 2 H) AN-(3-chloro-5-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 444

(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(4- (methylsulfonyl)picolino)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 526.0 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.77- 9.05 (m, 1 H), 8.52-8.74 (m, 1H), 8.12-8.25 (m, 1 H), 8.03 (ddd, J = 13.88, 5.06, 1.82 Hz, 1 H), 7.55-7.75 (m, 3 H), 4.88-5.53 (m, 1 H), 4.14-4.65 (m, 1 H), 3.76-3.95 (m, 1H), 3.40 (d, J = 5.97 Hz, 4 H), 2.52-2.78 (m, 2 H), 1.50- 1.92 (m, 2 H),0.43-1.25 (m, 4 H),-0.19-0.42 (m, 3 H) C 445

LCMS-ESI (POS.) m/z: 506.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.15- 8.56 (m, 1 H), 3.99-4.49 (m, 5 H), 3.86-3.97 (m, 2 H), 3.73-3.82(m, 1 H), 3.40-3.72 (m, 4 H), 2.62- 2.87 (m, 3 H), 2.18 (s, 7 H),2.02-2.12 (m, 1 H), 1.85-1.98 (m, 3 H), 1.67- 1.84 (m, 3 H), 1.35-1.54(m, 2 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-3,5- dimethylbenzyl)-D-prolinamide 446

N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4,4-difluoro-1-(3-sulfamoylbenzoyl)-D-prolinamide LCMS-ESI (POS.) m/z: 550.0 (M + H)⁺ 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 8.04-8.14 (m, 2 H), 7.69- 7.76 (m, 1H), 7.61-7.69 (m, 1 H), 7.54 (br d, J = 6.12 Hz, 1 H), 7.38-7.50 (m, 2H), 7.35 (br d, J = 10.47 Hz, 1 H), 5.32-5.67 (m, 2 H), 5.00 (br t, J =8.19 Hz, 1 H), 4.56 (br t, J = 7.93 Hz, 1 H), 3.93-4.08 (m, 1 H), 3.72-3.85 (m, 1 H), 2.83-3.01 (m, 1 H), 2.51-2.68 (m, 1 H), 1.21-1.33 (m, 1H), 0.49-0.66 (m, 2 H), 0.31- 0.49 (m, 2 H) C 447

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-cyclopropylbenzyl)-D- prolinamide LCMS-ESI(POS.) m/z: 500.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.08-7.15 (m, 2 H), 6.99- 7.06 (m, 2 H), 4.56 (br dd, J = 7.79, 2.60 Hz,1 H), 4.29 -4.45 (m, 2 H), 3.99-4.14 (m, 4 H), 3.69-3.78 (m, 2 H),3.50-3.65 (m, 2 H), 3.39-3.47 (m, 1 H), 2.83- 3.02 (m, 1 H), 2.65-2.83(m, 2 H), 2.37-2.43 (m, 1 H), 2.16-2.22 (m, 1 H), 2.00-2.07 (m, 1 H),1.86- 1.95 (m, 3 H), 1.77-1.84 (m, 1 H), 1.40-1.71 (m, 3 H), 0.91-0.99(m, 2 H), 0.62-0.72 (m, 2 H) C 448

LCMS-ESI (POS.) m/z: 526.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.40- 8.75 (m, 1 H), 7.52 (br d, J = 7.79 Hz, 2 H), 7.33- 7.43 (m, 2 H),6.87-7.16 (m, 1 H), 4.55-4.80 (m, 1 H), 4.30-4.45 (m, 3 H), 4.00-4.14(m, 3 H), 3.87- 3.98 (m, 2 H), 3.71-3.86 (m, 3 H), 3.50-3.68 (m, 1 H),3.24-3.50 (m, 2 H), 2.69-2.98 (m, 3 H), 1.78- 1.95 (m, 1 H), 1.64-1.76(m, 1 H), 1.46-1.62 (m, 1 H), 1.31-1.46 (m, 1 H), 1.31-1.46 (m, 1 H) B(3R)-4-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(difluoromethyl)benzyl)-3-morpholinecarboxamide 449

N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(3-((3-hydroxy-1-azetidinyl)sulfonyl)benzoyl)-D- prolinamide LCMS-ESI (POS.)m/z: 530.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.90- 8.03 (m, 2H),7.75-7.86 (m, H), 7.64-7.72 (m, 1H), 7.48-7.63 (m, 1H), 7.36- 7.45 (m,1H), 7.33 (br d, J = 9.95 Hz, 1H), 7.22 (br t, J = 5.60 Hz, 1H), 4.74(dd, J = 5.34, 7.20 Hz, 1H), 4.55- 4.66 (m, 2H), 4.50 (quin, J = 5.96Hz, 1H), 4.31-4.38 (m, 1H), 4.00-4.12 (m, 2H), 3.57-3.68 (m, 2H), 3.45-3.54 (m, 2H), 2.35-2.47 (m, 1H), 2.03-2.22 (m, 2H), 1.86-1.99 (m, 1H) B450

LCMS-ESI (POS.) m/z: 561.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.29-8.76 (m, 1H), 7.60-7.75 (m, 2H), 7.38-7.53 (m, 2H), 4.26- 4.51 (m,3H), 3.49-3.93 (m, 8H), 2.60-2.87 (m, 3H), 2.05-2.36 (m, 1H), 1.66- 2.03(m, 5H), 1.29-1.57 (m, 3H), 0.55-0.71 (m, 2H), 0.36-0.55 (m, 2H) JChiral 1-(((3S)-1-((3-cyclopropyl-3-fluoro-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 451

LCMS-ESI APCI (POS.) m/z: 628.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 7.36- 7.80 (m, 7 H), 4.69-4.97 (m, 4 H), 4.09-4.65 (m, 6 H),3.45-3.74 (m, 2 H), 2.24-2.38 (m, 1 H), 1.78- 2.00 (m, 3 H), 1.21-1.36(m, 1 H), 0.37-0.73 (m, 4 H). W N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(3-fluoro-1-(3-oxetanylsulfonyl)-3-azetidinyl)benzoyl)-D-prolinamide 452

LCMS-ESI (POS.) m/z: 488.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.99- 8.53 (m, 1 H), 7.03-7.24 (m, 4 H), 4.78-4.97 (m, 1 H), 4.25-4.47(m, 1 H), 4.01-4.13 (m, 2 H), 3.71- 4.00 (m, 4 H), 3.47-3.66 (m, 4 H),2.62-2.90 (m, 3 H), 2.02-2.39 (m, 4 H), 1.63-1.98 (m, 6 H), 1.34- 1.55(m, 3 H) A (2R)-1-((S)-1-( (3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(1-(p-tolyl)ethyl)pyrrolidine-2-carboxamide 453

N-((1R)-1-(4-chloro-2,5-difluorophenyl)propyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide LCMS-ESI (POS.) m/z: 485.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.20- 8.50 (m, 1 H), 7.59-8.11(m, 1 H), 7.51-8.12 (m, 4 H), 7.19-7.48 (m, 1 H), 4.56-5.02 (m, 1 H),4.29- 4.54 (m, 1 H), 3.41-3.64 (m, 2 H), 3.20-3.36 (m, 3 H), 2.15-2.33(m, 1 H), 1.32-1.96 (m, 5 H), 0.44- 0.96 (m, 3 H) A 454

LCMS-ESI (POS.) m/z: 531.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.42- 8.73 (m, 1 H), 7.09-7.91 (m, 13 H), 4.56-4.79 (m, 2 H), 4.10-4.51(m, 3 H), 3.35-3.68 (m, 1 H), 3.09- 3.30 (m, 1 H), 2.16-2.35 (m, 1 H),1.71-1.99 (m, 3 H) C 1-(3-(benzylsulfonyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 455

LCMS-ESI (POS.) m/z: 509.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.87-7.95 (m, 2 H), 7.52- 7.72 (m, 3 H), 7.44-7.51 (m, 3 H), 7.09 (br s,1 H), 5.21 (br d, J = 6.55 Hz, 1 H), 4.60 (br dd, J = 15.02, 5.94 Hz, 1H), 4.45 (dd, J = 15.18, 5.71 Hz, 1 H), 4.13 (t, J = 8.47 Hz, 2 H), 4.01(br s, 2 H), 3.28-3.43 (m, 1 H), 2.89-3.07 (m, 3 H), 2.00 (s, 1 H),1.71- 1.94 (m, 1 H), 1.51 (br d, J = 6.81 Hz, 3 H) C3-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-((3-(trifluoromethyl)benzyl)amino)ethyl)benzamide 456

(1R,3R,5R)-2-(3-(1-cyanocyclopropyl)benzoyl)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3- LCMS-ESI APCI (POS.) m/z:528.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 7.77 (q, J = 1.6 Hz,1 H), 7.69- 7.74 (m, 1 H), 7.48-7.59 (m, 5 H), 5.65 (d, J = 10.1 Hz, 1H), 4.99 (dd, J = 4.2, 11.4 Hz, 1 H), 4.61-4.70 (m, 2 H), 4.40 (t, J =0.9, 12.5 Hz, 1 H), 3.50-3.61 (m, 1 H), 3.29 (dd, J = 2.7, 6.3 Hz, 1 H),2.60-2.69 (m, 1 H), 2.05 (s, 1 H), 1.91 (dd, J = 4.2, 13.6 Hz, 1 H),1.75-1.82 (m, 3 H), 1.51-1.63 (m, 2 H), 1.23 (td, J = 2.6, 5.3 Hz, 1 H),0.84-0.91 (m, 1 H). Q carboxamide 457

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-4- methoxybenzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 508.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm6.88-7.02 (m, 3 H), 4.59 (dd, J = 8.04, 1.82 Hz, 1 H), 4.41 (dd, J =15.05, 6.49 Hz, 1 H), 4.27 (dd, J = 15.05, 5.45 Hz, 1 H), 4.08-4.16 (m,4 H), 3.88-3.91 (m, 3 H), 3.70-3.81 (m, 2 H), 3.54-3.64 (m, 2 H), 3.40-3.48 (m, 1 H), 2.97 (dd, J = 12.46, 11.16 Hz, 1 H), 2.67-2.81 (m, 2 H),2.42- 2.49 (m, 1 H), 2.15-2.31 (m, 1 H), 2.02-2.09 (m, 1 H), 1.79-1.98(m, 3 H), 1.51-1.70 (m, 4 H) C 458

(1R,3R,5R)-2((5-(cyclopropylamino)-2-methyl-4-pyridinyl)carbonyl)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2- azabicyclol3.1.0lhexane-3-carboxamideLCMS-ESI APCI (POS.) m/z: 517.2 (M + H)⁺ 1H NMR (400 MHz, MethyleneChloride-d2) δ ppm 8.49 (s, 1 H), 7.46- 7.56 (m, 2 H), 7.40 (d, J = 15.5Hz, 2 H), 6.80 (d, J = 7.0 Hz, 1 H), 6.50 (s, 1 H), 5.03 (dd, J = 2.8,11.2 Hz, 1 H), 4.53 (dd, J = 7.0, 9.0 Hz, 1 H), 3.12 (td, J = 2.6, 6.2Hz, 1 H), 2.69 (s, 3 H), 2.48-2.61 (m, 2 H), 2.19 (dd, J = 2.8, 13.4 Hz,1 H), 1.68-1.78 (m, 1 H), 1.25- 1.35 (m, 1 H), 0.93-0.98 (m, 1 H),0.85-0.93 (m, 2 H), 0.63-0.76 (m, 2 H), 0.59 (dddd, J = 3.1, 4.6, 6.4,9.9 Hz, 3 H), 0.36- 0.51 (m, 2 H). S 459

LCMS-ESI (POS.) m/z: 502.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.46- 8.73 (m, 1 H), 7.90 (d, J = 1.30 Hz, 7 H), 4.18- 4.54 (m, 3 H),3.44-3.65 (m, 2 H), 2.55-2.68 (m, 6 H), 2.21-2.33 (m, 1 H), 1.74-1.99(m, 3 H) A 1-(3-(dimethylsulfamoyl)benzoyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide 460

LCMS-ESI (POS.) m/z: 535.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.58- 8.79 (m, 2H), 7.66-8.01 (m, 6H), 4.10-4.58 (m, 5H), 3.20-3.47 (m,2H), 2.56- 2.68 (m, 4H), 2.02-2.29 (m, 1H), 1.22-1.79 (m, 5H) L(R)-1-(3-((3-cyanocyclobutyl)sulfonyl)benzoyl)-N-((6-(trifluoromethyl)pyridin-3- yl)methyl)piperidine-2-carboxamide 461

LCMS- APCI (NEG.) m/z: 530.1 (M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm8.17 (d, J = 1.7 Hz, 1 H), 8.01 (ddt, J = 1.3, 7.7, 15.0 Hz, 2 H), 7.79(t, J = 7.8 Hz, 1 H), 7.44-7.68 (m, 5 H), 4.56-4.73 (m, 2 H), 4.46 (d, J= 15.7 Hz, 1 H),4.18 -4.29 (m, 6 H), 3.67 (dt, J = 6.9, 10.3 Hz, 1 H),3.53 (ddd, J = 4.4,7.1, 10.1 Hz, 1 H), 2.30-2.48 (m, 1 H), 2.00-2.08 (m,2 H), 1.32 (dd, J = 6.6, 8.6 Hz, 1 H). Q1-((3-((3,3-difluoro-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 462

N-((1S)-1-(4-chloro-3-fluorophenyl)ethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide LCMS-ESI (POS.) m/z: 526.2 (M + H)⁺1H NMR (500 MHz, DMSO-d6) δ ppm 8.51- 8.56* (m, 1 H), 8.28 (d, J = 8.04Hz, 1 H), 7.51 (t, J = 8.04 Hz, 1 H), 7.33- 7.41 (m, 1 H), 7.14-7.21 (m,1 H), 4.81-4.96 (m, 1 H), 4.42* (br d, J = 8.69 Hz, 1 H), 4.25-4.32 (m,1 H), 4.00-4.08 (m, 2 H), 3.89- 3.96 (m, 2 H), 3.79 (ddd, J = 14.89,8.79, 6.42 Hz, 1 H), 3.49-3.64 (m, 3 H), 3.43 (m, 1 H), 2.72-2.87 (m, 2H), 2.59-2.68 (m, 1 H), 2.14-2.28* (m, 1 H), 2.02-2.10* (m, 1 H), 1.92-1.99 (m, 1 H), 1.65-1.92 (m, 5 H), 1.37-1.53 (m, 2 H), 1.29-1.37 (m, 3H). Spectrum appears as 2:1 mixture of rotamers, *denotes resolved minorrotamer peaks. C 463

LCMS-ESI (POS.) m/z: 597.4 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.31-8.78 (m, 1H), 7.33-7.80 (m, 9H), 4.18-4.52 (m, 7H), 3.51- 3.74 (m,4H), 2.76-2.97 (m, 2H), 2.60-2.73 (m, 1H), 2.02-2.39 (m, 1H), 1.67- 2.02(m, 5H), 1.37-1.58 (m, 2H) J 1-(((3S)-1-((3-fluoro-3-phenyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 464

LCMS-ESI (POS.) m/z: 531.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.74(d, J = 7.40 Hz, 1 H), 7.46- 8.16 (m, 6 H), 4.52-4.67 (m, 1 H),4.12-4.32 (m, 1 H), 3.50-3.64 (m, 1 H), 3.24-3.38 (m, 4 H), 2.15- 2.28(m, 1 H), 1.66-1.88 (m, 3 H), 0.84-1.24 (m, 1 H),-0.11-0.64 (m, 4 H) CN-((R)-((R) -fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(2-fluoro-5-(methylsulfonyl)benzoyl)-D-prolinamide 465

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide LCMS-ESI (POS.) m/z: 542.2(M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.34-7.55 (m, 5 H), 5.03(quin, J = 7.07 Hz, 1 H), 4.56 (dd, J = 8.04, 2.08 Hz, 1 H), 4.06-4.15(m, 4 H), 3.74-3.80 (m, 2 H), 3.71 (br d, J = 12.85 Hz, 1 H), 3.53-3.64(m, 2 H), 3.43 (tt, J = 8.68, 6.50 Hz, 1 H), 3.00 (dd, J = 12.59, 11.16Hz, 1 H), 2.67-2.83 (m, 2 H), 2.28-2.41 (m, 1 H), 2.09-2.22 (m, 1 H),1.96- 2.06 (m, 2 H), 1.75-1.92 (m, 2 H), 1.57-1.71 (m, 2 H), 1.44 (d, J= 7.01 Hz, 3 H) A 466

LCMS-ESI (POS.) m/z: 540.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ7.39- 8.06 (m, 8H), 7.04-7.18 (m, 1H), 4.84-5.21 (m, 1H), 4.33-4.76 (m,1H), 3.95- 4.26 (m, 3H), 3.72-3.80 (m, 2H), 3.36-3.72 (m, 4H), 2.25-2.42(m, 1H), 2.08- 2.19 (m, 2H), 1.83-1.97 (m, 1H), 1.51-1.56 (m, 3H),1.24-1.34 (m, 1H) C 1-(3-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide 467

1-(((3S)-1-((3-hydroxy-3-(trifluoromethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 587.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (d, J = 8.04 Hz, 2 H),7.28-7.43 (m, 2 H), 7.14- 7.26 (m, 1 H), 4.37-4.58 (m, 3 H), 3.94-4.20(m, 4 H), 3.50-3.76 (m, 4 H), 3.02 (dd, J = 12.46, 10.12 Hz, 1 H),2.79-2.92 (m, 1 H), 2.71 (qd, J = 6.79, 3.76 Hz, 1 H), 2.30-2.45 (m, 1H), 2.13-2.27 (m, 1 H), 1.74-2.10 (m, 5 H), 1.47- 1.71 (m, 5 H),1.19-1.36 (m, 2 H) M 468

LCMS-ESI (POS.) m/z: 524.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.13(d, J = 8.30 Hz, 1 H), 6.96- 7.11 (m, 3 H), 4.62-4.80 (m, 1 H),4.29-4.48 (m, 1 H), 3.89-4.09 (m, 4 H), 3.74-3.85 (m, 2 H), 3.57 (br d,J = 6.88 Hz, 2 H), 2.80 (br d, J = 11.55 Hz, 3 H), 1.21-2.15 (m, 11 H),0.75- 0.91 (m, 3 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(3,5-difluorophenyl)propyl)-D-prolinamide 469

1-(((3S)-1-((3-((4-fluorophenyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- LCMS-ESI (POS.) m/z:612.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ 8.27-8.76 (m, 1H), 7.61-7.73(m, 2H), 7.38-7.50 (m, 2H), 6.87- 7.00 (m, 2H), 6.45-6.58 (m, 2H),6.17-6.28 (m, 1H), 4.25-4.52 (m, 3H), 4.04- 4.20 (m, 3H), 3.50-3.71 (m,6H), 2.71-2.90 (m, 2H), 2.60-2.71 (m, 1H), 2.03- 2.38 (m, 1H), 1.67-2.00(m, 5H), 1.36-1.57 (m, 2H) J (trifluoromethyl)benzyl)-D-prolinamide 470

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-pyrrolidinyl)carbonyl)-N-(2-fluoro-4- LCMS-ESI (POS.) m/z: 532.2 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.42- 7.52 (m, 1H), 7.29-7.42 (m,3H), 4.59 (dd, J = 2.33, 8.14 Hz, 1H), 4.45-4.55 (m, 2H), 4.10-4.23 (m,4H), 3.38-3.67 (m, 7H), 3.23 (quin, J = 6.92 Hz, 1H), 2.35-2.45 (m, 1H),2.14- 2.25 (m, 2H), 2.00-2.12 (m, 2H), 1.85-1.99 (m, 1H) M(trifluoromethyl)benzyl)-D-prolinamide 471

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((4-cyclopropyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 488.1 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.50 (dd, J = 0.9, 5.1 Hz, 1 H),7.50 (dd, 1 H), 7.36-7.47 (m, 2 H), 7.27 (dd, J = 6.3, 9.4 Hz, 1 H),5.57 (d, J = 10.3 Hz, 1 H), 4.91-5.00 (m, 1 H), 4.84 (dd, J = 6.5, 7.7Hz, 1 H), 4.67 (dd, J = 6.4, 7.8 Hz, 1 H), 4.60 (t, J = 6.2 Hz, 1 H),4.38 (t, J = 6.2 Hz, 1 H), 3.45-3.56 (m, 1 H), 3.27 (td, J = 2.6, 6.2Hz, 1 H), 2.66 (td, J = 6.6, 12.7 Hz, 1 H), 2.12- 2.22 (m, 1 H), 1.89(dd, J = 4.1, 13.6 Hz, 1 H), 1.72- 1.85 (m, 1 H), 1.23 (td, J = 2.6, 5.3Hz, 1 H), 0.97- 1.13 (m, 4 H), 0.85 (dt, J = 5.8, 8.7 Hz, 1 H). Q 472

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-(4-methyl-3-(methylsulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 539.1 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (d,J = 8.2 Hz, 1 H), 8.28 (d, J = 1.8 Hz, 1 H), 7.89-7.95 (m, 1 H), 7.66(dd, J = 6.2, 9.4 Hz, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.44 (dd, J =6.2, 9.7 Hz, 1 H), 5.41 (t, J = 9.0 Hz, 1 H), 4.88 (dd, J = 3.8, 11.4Hz, 1 H), 4.62 (dd, J = 6.4, 7.7 Hz, 1 H), 4.51 (dd, J = 6.2, 7.8 Hz, 1H), 4.36 (t, J = 6.1 Hz, 1 H), 4.19 (t, J = 6.1 Hz, 1 H), 3.27 (s, 4 H),2.70 (s, 3 H), 2.52-2.58 (m, 1 H), 1.70 (dd, J = 3.9, 13.4 Hz, 2 H),1.16 (ddd, J = 2.0, 4.7, 7.5 Hz, 1 H), 0.79 (dt, J = 5.3, 9.6 Hz, 1 H).Q 473

LCMS-ESI (POS.) m/z: 574.4 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.29-8.77 (m, 1H), 7.61-7.98 (m, 3H), 7.37-7.55 (m, 2H), 6.73- 7.06 (m,1H), 4.24-4.50 (m, 3H), 3.83-4.01 (m, 1H), 3.42-3.72 (m, 4H), 3.01- 3.19(m, 2H), 2.55-2.78 (m, 3H), 1.11-2.36 (m, 14H) J(2R)-1-((3S)-1-(N-(2-oxoazepan-3-yl)sulfamoyl)piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide 474

1-((3-((4-methoxy-1- piperidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 554.2 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.91 (s, 1 H), 7.85 (br d, J =7.93 Hz, 1 H), 7.73 (d, J = 7.72 Hz, 1 H), 7.54- 7.66 (m, 3 H), 7.42 (d,J = 8.03 Hz, 2 H), 7.28- 7.35 (m, 1 H), 4.76 (dd, J = 7.31, 5.08 Hz, 1H), 4.55 (d, J = 5.96 Hz, 2 H), 3.60 (dt, J = 10.33, 6.68 Hz, 1 H), 3.46(dt, J = 10.06, 6.40 Hz, 1 H), 3.38 (s, 1 H), 3.24- 3.32 (m, 4 H),3.10-3.21 (m, 2 H), 2.96-3.09 (m, 2 H), 2.33-2.57 (m, 1 H), 2.14 (br d,J = 5.23 Hz, 2 H), 2.00-2.01 (m, 1 H), 1.85- 1.91 (m, 3 H), 1.66-1.82(m, 2 H) B 475

(1R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azaspiro[3.3]heptane- 1-carboxamide LCMS-ESI(POS.) m/z: 539.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm8.17-8.37 (m, 1 H), 7.91- 8.17 (m, 2 H), 7.60-7.83 (m, 1 H), 7.44-7.57(m, 1 H), 7.36-7.44 (m, 1 H), 7.29-7.36 (m, 1 H), 7.01- 7.24 (m, 1 H),4.72-4.79 (m, 1 H), 4.48-4.71 (m, 1 H), 4.28-4.48 (m, 1 H), 4.10-4.28(m, 1 H), 2.91- 3.25 (m, 3 H), 2.27-2.60 (m, 2 H), 2.09-2.25 (m, 1 H),1.98-2.08 (m, 1 H), 1.89-1.97 (m, 1 H), 1.76- 1.89 (m, 1 H), 1.20-1.34(m, 1 H), 0.61-0.74 (m, 1 H), 0.53-0.61 (m, 1 H), 0.26-0.52 (m, 2 H) C476

(3R,5R)-5-(((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)carbamoyl)-1-((2-(difluoromethyl)-4-pyridinyl)carbonyl)-3- LCMS- APCI (POS.) m/z: 657.1(M + H)⁺ 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.79 (d, J = 3.2, 5.1 Hz, 1 H),8.75 (d, J = 5.0 Hz, 1 H), 8.49 (d, J = 8.2 Hz, 1 H), 7.75- 7.79 (m, 2H), 7.71 (ddd, J = 1.4, 5.1, 9.1 Hz, 1 H), 7.61-7.66 (m, 1 H), 7.27-7.35 (m, 1 H), 7.15 (td, J = 2.6, 6.3, 7.1 Hz, 2 H), 6.86 -7.11 (m, 3H), 5.50-5.57 (m, 1 H), 5.17 (dd, J = 8.2, 9.7 Hz, 1 H), 4.53 (d, J =9.1 Hz, 1 H), 4.26-4.41 (m, 3 H), 3.87-3.96 (m, 3 H), 3.82 (t, J = 6.1Hz, 1 H), 3.00-3.12 (m, 1 H), 2.81 (ddd, J = 4.5, 9.3, 14.1 Hz, 1 H),2.28 (d, J = 14.4 Hz, 1 H). U pyrrolidinyl 2-(difluoromethyl)-4-pyridinecarboxylate 477

LCMS-ESI (POS.) m/z: 597.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.26-8.76 (m, 1H), 7.60-7.73 (m, 2H), 7.34-7.51 (m, 4H), 7.11- 7.26 (m,2H), 4.22-4.52 (m, 3H), 4.08-4.22 (m, 2H), 3.76-3.92 (m, 3H), 3.41- 3.71(m, 4H), 2.70-2.90 (m, 2H), 2.59-2.70 (m, 1H), 2.02-2.40 (m, 1H), 1.65-2.02 (m, 5H), 1.33-1.59 (m, 2H) J 1-(((3S)-1-((3-(4-fluorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 478

LCMS-ESI (POS.) m/z: 496.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.55- 8.88 (m, 1 H), 7.22-7.92 (m, 8 H), 4.70-4.75 (m, 1 H), 4.67-4.79(m, 1 H), 4.19-4.53 (m, 2 H), 3.81- 3.95 (m, 1 H), 3.31-3.64 (m, 1 H),2.56-2.69 (m, 6 H), 1.57-1.76 (m, 2 H), 0.22-0.87 (m, 2 H) C(1R,2R,5S)-3-(3-(dimethylsulfamoyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-3- azabicyclo[3.1.0]hexane-2-carboxamide 479

N-((R)-(4-chloro-2- fluorophenyl)(cyclopropyl)methyl)-1-(3- LCMS-ESI(POS.) m/z: 479.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.40- 8.65(m, 1 H), 7.63-8.08 (m, 4 H), 7.24-7.52 (m, 3 H), 4.14-4.59 (m, 2 H),3.39-3.62 (m, 2 H), 3.24- 3.29 (m, 3 H), 2.13-2.26 (m, 1 H), 1.65-1.89(m, 3 H), 0.85-1.23 (m, 1 H), − 0.08-0.58 (m, 4 H) A(methylsulfonyl)benzoyl)-D-prolinamide 480

(1R,3R,5R)-2((2-(difluoromethyl)-4-pyridinyl)carbonyl)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 514.1 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.69 (d, J = 0.7, 5.0 Hz, 1 H),7.89 (s, 1 H), 7.75 (d, J = 0.9, 1.7, 5.0 Hz, 1 H), 7.35 -7.47 (m, 3 H),6.70 (t, J = 55.1 Hz, 1 H), 5.54 (d, J = 10.1 Hz, 1 H), 4.87 (dd, J =4.1, 11.4 Hz, 1 H), 4.71- 4.78 (m, 6 H), 4.50-4.58 (m, 2 H), 4.28 (t, 1H), 3.40 -3.50 (m, 1 H), 3.17 (ddd, J = 2.6, 5.9, 6.6 Hz, 1 H),2.50-2.60 (m, 1 H), 1.79 (dd, 1 H), 1.65-1.72 (m, 1 H), 1.13 (tt, J =2.6, 5.4 Hz, 1 H), 0.75 (ddd, J = 4.8, 5.9, 8.5 Hz, 1 H). A 481

(2R)-1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-LCMS-ESI (POS.) m/z: 569.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.87- 8.09 (m, 3 H), 7.87 (br s, 1 H), 7.77-7.84 (m, 1 H), 7.71 (br d, J= 7.66 Hz, 1 H), 7.60-7.67 (m, 2 H), 7.56 (br d, J = 7.66 Hz, 1 H), 7.44(br s, 1 H), 7.36 (br d, J = 7.27 Hz, 1 H), 7.21- 7.31 (m, 2 H),7.15-7.21 (m, 1 H), 7.07-7.15 (m, 1 H), 6.88-7.07 (m, 1 H), 4.27 (br s,1 H), 4.08 (br d, J = 5.06 Hz, 1 H), 3.94- 4.04 (m, 2 H), 3.80-3.93 (m,2 H), 3.05 (s, 1 H) I (trifluoromethyl)benzyl)-2,3-dihydro-1H-indole-2-carboxamide, (2S)-1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-indole-2- carboxamide 482

LCMS-ESI (POS.) m/z: 538.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.32- 8.72 (m, 1H), 7.37-8.12 (m, 9H), 4.56-5.05 (m, 1H), 4.31-4.56 (m,1H), 3.41- 3.65 (m, 2H), 3.23-3.30 (m, 3H), 2.93-3.01 (m, 1H), 2.73-2.93(m, 1H), 2.53- 2.69 (m, 1H), 2.11-2.27 (m, 2H), 1.55-1.92 (m, 4H) ADiastereomer #2-(1R,3R,5R)-N-((2-fluoro-4-(trifluoromethyl)phenyl)(5-oxopyrrolidin-3-yl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 483

LCMS-ESI (POS.) m/z: 557.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.28-8.81 (m, 1H), 7.61-7.74 (m, 2H), 7.37-7.52 (m, 2H), 4.24- 4.52 (m,3H), 3.71-3.87 (m, 2H), 3.42-3.71 (m, 7H), 2.58-2.83 (m, 4H), 2.06- 2.35(m, 1H), 1.59-2.04 (m, 11H), 1.30-1.54 (m, 2H) J1-(((3S)-1-((3-cyclobutyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 484

(1S,2R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-(3- (methylsulfonyl)benzoyl)-3-azabicyc1o[3.1.0]hexane-2-carboxamide LCMS-ESI (POS.) m/z: 525.0 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.89-8.14 (m, 2 H), 7.73- 7.85(m, 1 H), 7.56-7.71 (m, 1 H), 7.29-7.52 (m, 3 H), 5.93-6.60 (m, 1 H),4.69 (d, J = 5.60 Hz, 1 H), 4.50-4.63 (m, 1 H), 3.49- 4.13 (m, 2 H),2.97-3.18 (m, 3 H), 1.92-2.09 (m, 1 H), 1.68-1.80 (m, 1 H), 1.14-1.32(m, 1 H), 0.35- 1.02 (m, 6 H) C 485

(1R,3R,5R)-N-((R)-(4-chloro-3- fluorophenyl)(cyclopropyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS-ESI (POS.) m/z: 491.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.30- 8.68 (m, 1 H), 7.86-8.21 (m, 3 H), 7.64-7.83 (m, 1 H), 7.48-7.59(m, 1 H), 7.33-7.43 (m, 1 H), 7.17- 7.30 (m, 1 H), 4.63-4.97 (m, 1 H),4.17-4.28 (m, 1 H), 3.20-3.30 (m, 4 H), 2.55-2.69 (m, 1 H), 1.65- 1.97(m, 2 H), 1.02-1.29 (m, 2 H), 0.68-0.81 (m, 1 H),-0.36-0.53 (m, 4 H) C486

LCMS-ESI (POS.) m/z: 496.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.44- 8.75 (m, 1 H), 7.07-7.98 (m, 8 H), 4.17-4.55 (m, 3 H), 3.69 (br t,J = 7.79 Hz, 4 H), 3.17 (br d, J = 6.36 Hz, 1 H), 2.62-2.68 (m, 1 H),2.24-2.32 (m, 1 H), 2.01- 2.02 (m, 1 H), 1.81-2.04 (m, 5 H), 0.94-1.07(m, 10 H) C 1-(3-(1-azetidinylsulfonyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 487

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((6-(trifluoromethyl)-4-pyrimidinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 517.1 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 9.51 (d, J = 1.3, 80.7 Hz, 1 H),8.61 (d, J = 8.3, 55.4 Hz, 1 H), 8.20 (d, J = 1.3, 17.1 Hz, 1 H), 7.65(ddd, J = 6.2, 9.5, 15.8 Hz, 1 H), 7.37 (dd, J = 6.4, 9.8, 62.4 Hz, 1H), 5.37-5.47 (m, 1 H), 4.83- 5.18 (m, 1 H), 4.58 (dt, J = 7.3, 49.2 Hz,1 H), 4.18- 4.45 (m, 2 H), 3.78-3.88 (m, 1 H), 1.58-1.89 (m, 2 H),1.08-1.14 (m, 1 H), 0.60-0.84 (m, 1 H). Q 488

(4S)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-4-fluoro-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D- LCMS-ESI (POS.) m/z: 516.0(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 9.20 (d, J = 2.08 Hz, 1 H),9.06 (d, J = 1.82 Hz, 1 H), 8.59- 8.83 (m, 1 H), 8.41 (t, J = 1.95 Hz, 1H), 7.30- 7.67 (m, 2 H), 5.20-5.46 (m, 1 H), 3.95-4.74 (m, 3 H), 3.74(br s, 2 H), 3.37- 3.45 (m, 3 H), 1.82-2.16 (m, 1 H), 0.81-1.32 (m, 1H),-0.35-0.73 (m, 4 H) C prolinamide 489

LCMS-ESI (POS.) m/z: 614.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) 68.29-8.79 (m, 1H), 7.62-7.76 (m, 2H), 7.40-7.51 (m, 2H), 4.27- 4.60 (m,4H), 3.82-4.06 (m, 4H), 3.51-3.75 (m, 5H), 2.70-2.91 (m, 2H), 2.60- 2.70(m, 1H), 2.02-2.37 (m, 1H), 1.68-2.02 (m, 5H), 1.33-1.58 (m, 2H) J1-(((3S)-1-((3-((trifluoroacetyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 490

LCMS-ESI (POS.) m/z: 526.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.50- 9.03 (m, 2 H), 8.11-8.25 (m, 1 H), 7.98-8.10 (m, 1 H), 7.53-7.75(m, 3 H), 4.90-5.53 (m, 1 H), 4.14- 4.68 (m, 1 H), 3.78-3.99 (m, 1 H),3.40 (br d, J = 5.71 Hz, 3 H), 2.54-2.80 (m, 1 H), 1.50-1.90 (m, 2 H),−0.17-1.24 (m, 7 H) C (1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((6-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 491

(1R,3R,5R)-N-((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(cyclopropylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 552.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.19-9.32 (m, 2 H), 8.55- 8.65(m, 1 H), 7.57-7.66 (m, 1 H), 7.33-7.41 (m, 1 H), 7.18-7.28 (m, 2 H),5.11-5.24 (m, 1 H), 4.31- 4.45 (m, 1 H), 3.27-3.35 (m, 1 H), 2.53-2.66(m, 2 H), 2.37-2.50 (m, 1 H), 1.82-1.90 (m, 1 H), 1.42- 1.54 (m, 2 H),1.10-1.30 (m, 4 H), 0.95-1.02 (m, 1 H), 0.56-0.72 (m, 2 H), 0.38-0.50(m, 2 H) H 492

1-(((3S)-1-((3-methoxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 533.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.72* (t, J = 5.77 Hz, 1 H), 8.36 (t, J = 5.97 Hz, 1 H), 7.65- 7.71 (m,2 H), 7.45 (d, J = 7.98 Hz, 2 H), 4.28- 4.49 (m, 3 H), 4.16 (quin, J =5.61 Hz, 1 H), 3.90- 3.97 (m, 2 H), 3.33-3.67 (m, 6 H), 3.19 (s, 3 H),2.69-2.84 (m, 2 H), 2.62- 2.69 (m, 1 H), 2.27-2.35* (m, 1 H), 2.18-2.26*(m, 1 H), 2.06-2.14 (m, 1 H), 1.67-2.00 (m, 5 H), 1.33- 1.55 (m, 2 H).Spectrum appears as 2:1 mixture of rotamers, *denotes resolved minorrotamer peaks. M 493

LCMS- APCI (POS.) m/z: 693.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.90 (q, J = 5.1 Hz, 2 H), 8.52 (d, J = 8.1 Hz, 1 H), 7.98-8.04 (m, 1H), 7.86-7.89 (m, 1 H), 7.77 (ddd, J = 1.4, 4.9, 10.5 Hz, 2 H),7.06-7.15 (m, 2 H), 5.57 (d, J = 3.9 Hz, 1 H), 5.09-5.20 (m, 1 H), 4.57(d, J = 9.2 Hz, 1 H), 4.31 (ddd, J = 6.1, 7.7, 14.1 Hz, 2 H), 3.87-3.96(m, 3 H), 3.77 (t, J = 6.1 Hz, 1 H), 3.06 (p, J = 7.1 Hz, 1 H), 2.81(ddd, J = 4.4, 9.4, 14.3 Hz, 1 H), 2.27-2.36 (m, 1H). T(3R,5R)-5-(((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)carbamo)-1-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-3- pyrrolidinyl2-(trifluoromethyl)-4- pyridinecarboxylate 494

LCMS-ESI (POS.) m/z: 560.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.44- 8.90 (m, 1 H), 7.51-7.65 (m, 4 H), 5.17-5.45 (m, 1 H), 4.89-5.08(m, 1 H), 4.36-4.68 (m, 1 H), 4.03- 4.12 (m, 2 H), 3.85-4.00 (m, 3 H),3.65-3.85 (m, 2 H), 3.54 (br d, J = 8.82 Hz, 2 H), 2.72-2.89 (m, 2 H),2.57-2.71 (m, 1 H), 2.34- 2.46 (m, 1 H), 1.67-2.09 (m, 3 H), 1.30-1.56(m, 5 H) C (2R,4S)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-4-fluoro-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-2- carboxamide 495

(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyc1o[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 516.2 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.94 (d, J = 4.9 Hz, 2 H), 8.65 (d,J = 7.5, 94.9 Hz, 2 H), 7.99 (t, J = 1.2 Hz, 1 H), 7.93 (d, 1 H),7.54-7.77 (m, 5 H), 4.94 (dd, J = 3.5, 11.4 Hz, 1 H), 4.53-4.69 (m, 2H), 4.35 (t, J = 5.1 Hz, 1 H), 4.12 (t, J = 8.3 Hz, 1 H), 3.71-3.81 (m,1 H), 3.28 (td, J = 2.8, 6.2 Hz, 1 H), 2.56-2.64 (m, 1 H), 1.57- 1.78(m, 3 H), 1.19 (dt, J = 4.9, 8.9 Hz, 2 H), 0.85- 0.95 (m, 1 H),0.66-0.78 (m, 2 H), 0.52-0.62 (m, 1 H), 0.46 (t, J = 9.1 Hz, 1H),0.21-0.39 (m, 3 H), − 0.29-0.00 (m, 2 H). Q 496

LCMS-ESI (POS.) m/z: 478.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.25- 8.69 (m, 1 H), 7.30-7.42 (m, 1 H), 6.96-7.14 (m, 3 H), 3.87-4.50(m, 6 H), 3.75-3.82 (m, 1 H), 3.42- 3.69 (m, 5 H), 2.60-2.89 (m, 3 H),2.06-2.34 (m, 1 H), 1.66-2.02 (m, 5 H), 1.35-1.60 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluorobenzyl)-D- prolinamide 497

(1R,3R,5R)-2-(3-(1-amino-2-methyl-1-oxo-2-propanyl)benzoyl)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 548.2 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 7.88 (t, J = 1.8 Hz, 1 H), 7.65(dt, J = 1.4, 7.5 Hz, 1 H), 7.56-7.59 (m, 1 H), 7.51- 7.56 (m, 2 H),7.44-7.50 (m, 2 H), 5.65 (d, J = 10.2 Hz, 1 H), 4.99 (dd, J = 4.2, 11.4Hz, 1 H), 4.83-4.86 (m, 1 H), 4.60-4.70 (m, 2 H), 4.40 (t, J = 0.9, 12.5Hz, 1 H), 3.51-3.61 (m, 1 H), 2.57-2.68 (m, 1 H), 1.91 (dd, J = 4.2,13.5 Hz, 1 H), 1.72-1.80 (m, 1 H), 1.60 (d, J = 4.1 Hz, 7 H), 1.22 (td,J = 2.6, 5.3 Hz, 1 H), 0.84-0.91 (m, 1 H). V 498

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-5- LCMS-ESI (POS.) m/z: 492.2 (M + H)⁺1H NMR (500 MHz, DMSO-d6) δ ppm 8.22- 8.65 (m, 1 H), 6.79-6.93 (m, 3 H),4.16-4.52 (m, 3 H), 3.98-4.09 (m, 2 H), 3.86-3.97 (m, 2 H), 3.73- 3.83(m, 1 H), 3.36-3.70 (m, 4 H), 2.70-2.87 (m, 2 H), 2.61-2.69 (m, 1 H),2.05-2.33 (m, 4 H), 1.67- 2.00 (m, 5 H), 1.35-1.55 (m, 2 H) Amethylbenzyl)-D-prolinamide 499

LCMS-ESI (POS.) m/z: 582.0 (M + H)⁺ 1H NMR (500 MHz, METHANOL-d4) δ ppm8.75-8.90 (m, 1 H), 8.11 (br d, J = 6.49 Hz, 1 H), 7.47-7.69 (m, 1 H),4.43- 4.77 (m, 3 H), 4.09-4.35 (m, 5 H), 3.44-3.84 (m, 4 H), 2.78-3.11(m, 6 H), 1.46- 2.66 (m, 9 H) A 1-(((3S)-1-((3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-D- prolinamide 500

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((2-(trifluoromethyl)-4-pyrimidinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 517.1 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (d, J = 5.1 Hz, 1 H), 9.24 (d,J = 5.2 Hz, 1 H), 8.69 (d, J = 8.2 Hz, 1 H), 8.53 (d, J = 8.0 Hz, 1 H),8.08 (t, J = 4.6 Hz, 2 H), 7.64 (ddd, J = 6.2, 9.4, 21.9 Hz, 2 H), 7.45(dd, J = 6.3, 9.8 Hz, 1 H), 7.29 (dd, J = 6.3, 9.7 Hz, 1 H), 5.38-5.46(m, 2 H), 5.03-5.10 (m, 1 H), 4.87 (dd, J = 3.5, 11.4 Hz, 1 H), 4.65 (t,1 H), 4.52 (t, 1 H), 4.32-4.42 (m, 3 H), 4.30 (t, 1 H), 4.21 (t, J = 6.1Hz, 2 H), 3.85 (t, J = 6.1 Hz, 1 H), 3.70-3.80 (m, 2 H), 3.65 (t, J =5.9 Hz, 1 H), 3.41-3.48 (m, 2 H), 3.15-3.26 (m, 2 H), 2.74-2.85 (m, 2H), 1.87 (dd, J = 2.7, 13.6 Hz, 1 H), 1.71 (dd, J = 3.8, 13.5 Hz, 2H),1.57-1.66 (m, 2 H), 1.11 (dd, J = 5.1, 7.7 Hz, 1 H), 1.06 (t, J = 7.0Hz, 2 H), 0.80 (q, J = 7.6 Hz, 2 H), 0.64-0.71 (m, 1 H), 0.38-0.49 (m, 1H). Q 501

(4R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-1-((2-(difluoromethyl)-4-pyridinyl)carbonyl)-4-hydroxy-D-prolinamide LCMS- APCI (POS.) m/z: 502.2(M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.80 (d, J = 4.9 Hz, 1 H),7.88 (t, J = 1.1 Hz, 1 H), 7.67- 7.76 (m, 1 H), 7.27-7.43 (m, 2 H), 6.81(t, J = 55.1 Hz, 1 H), 5.63 (d, J = 10.2 Hz, 1 H), 4.70 (dd, J = 6.4,7.8 Hz, 1 H), 4.55-4.68 (m, 3 H), 4.43 (q, J = 5.6, 6.1 Hz, 1 H), 4.34(p, J = 5.2 Hz, 1 H), 3.62-3.74 (m, 1 H), 3.49-3.60 (m, 1 H), 3.47 (dd,J = 4.7, 10.5 Hz, 1 H), 2.44-2.58 (m, 1 H), 1.84-1.97(m, 1 H). Q 502

LCMS-ESI (POS.) m/z: 502.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.98- 8.76 (m, 1 H), 7.02-7.22 (m, 2 H), 6.82-6.95 (m, 1 H), 6.70-6.81(m, 1 H), 4.89-5.07 (m, 1 H), 4.23- 4.48 (m, 1 H), 4.11-4.22 (m, 2 H),4.07 (br t, J = 8.43 Hz, 2 H), 3.89-4.00 (m, 2 H), 3.74-3.84 (m, 1 H),3.42-3.72 (m, 4 H), 2.60- 2.91 (m, 3 H), 2.17-2.40 (m, 1 H), 1.63-2.14(m, 7 H), 1.32-1.56 (m, 2 H) A(2R)-N-(chroman-4-)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)pyrrolidine-2- carboxamide 503

LCMS-ESI (POS.) m/z: 526.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ7.54- 7.64 (m, 2H), 7.45-7.52 (m, 1H), 7.33-7.44 (m, 2H), 7.28-7.32 (m,1H), 4.35- 4.70 (m, 3H), 4.12-4.27 (m, 3H), 3.13-3.79 (m, 6H), 2.41-2.57(m, 1H), 2.15- 2.33 (m, 1H), 2.00-2.15 (m, 1H), 1.56-1.99 (m, 2H),0.92-1.38 (m, 1H), 0.36- 0.90 (m, 1H) M(2R)-1-(2-((3-cyanoazetidin-1-yl)sulfonyl)-2-azabicyclo[3.1.0]hexane-4-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide 504

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((2-(2-propanyl)-4-pyridinyl)carbonyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS- APCI (POS.) m/z: 490.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 8.60 (dd, J = 0.9, 5.1 Hz, 1 H), 7.65 (t, J = 1.1 Hz, 1 H), 7.55(dd, J = 1.6, 5.1 Hz, 1 H), 7.39 (dd, J = 6.1, 9.5 Hz, 1 H), 7.27 (dd, J= 6.3, 9.4 Hz, 1 H), 5.57 (d, J = 10.2 Hz, 1 H), 4.95 (dd, J = 4.1, 11.4Hz, 1 H), 4.84 (dd, J = 6.5, 7.6 Hz, 1 H), 4.67 (dd, J = 6.4, 7.9 Hz, 1H), 4.61 (t, J = 6.2 Hz, 1 H), 4.38 (t, J = 0.8, 12.4 Hz, 1 H),3.45-3.56 (m, 1 H), 3.27 (td, J = 2.6, 6.2 Hz, 1 H), 3.16 (dt, J = 6.9,13.9 Hz, 1 H), 2.61-2.71 (m, 1 H), 1.90 (dd, J = 4.1, 13.5 Hz, 1 H),1.76-1.84 (m, 1 H), 1.35 (dd, J = 2.2, 6.9 Hz, 7 H), 1.24 (td, J = 2.6,5.3 Hz, 1 H), 0.85 (dtd, J = 1.1, 5.7, 9.0 Hz, 1 H). Q 505

LCMS-ESI (POS.) m/z: 514.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.78- 9.03 (m, 1 H), 8.60 (br d, J = 7.53 Hz, 1 H), 7.97- 8.25 (m, 2 H),7.52-7.78 (m, 3 H), 4.18-5.11 (m, 2 H), 3.61-3.82 (m, 2 H), 3.39 (br s,3 H), 2.09-2.29 (m, 1 H), 1.65-1.92 (m, 3 H), 1.03-1.24 (m, 1 H), −0.06-0.65 (m, 4 H) C N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((6-(methylsulfonyl)-3-pyridinyl)carbonyl)-D- prolinamidev 506

LCMS-ESI (POS.) m/z: 529.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.79(d, J = 7.40 Hz, 1 H), 7.36- 8.08 (m, 9 H), 4.25-4.65 (m, 2 H),4.09-4.22 (m, 1 H), 3.55-3.89 (m, 1 H), 3.20-3.29 (m, 3 H), 2.36- 2.45(m, 1 H), 1.55-1.70 (m, 1 H), 0.86-1.29 (m, 1 H),-0.12-0.62 (m, 4 H) C(4R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-hydroxy-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 507

LCMS-ESI (POS.) m/z: 521.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.38- 8.81 (m, 2H), 7.53-8.15 (m, 6H), 4.03-4.60 (m, 5H), 3.37-3.68 (m,3H), 3.13- 3.22 (m, 1H), 2.53-2.68 (m, 4H), 2.18-2.35 (m, 1H), 1.76-2.00(m, 3H) L (R)-1-(3-((3-cyanocyclobutyl)sulfonyl)benzoyl)-N-((6-(trifluoromethyl)pyridin-3- yl)methyl)pyrrolidine-2-carboxamide 508

LCMS-ESI (POS.) m/z: 492.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.19- 8.57 (m, 1 H), 7.12-7.22 (m, 1 H), 6.91-7.04 (m, 2 H), 4.29-4.53(m, 1 H), 4.12-4.29 (m, 2 H), 3.99- 4.10 (m, 2 H), 3.86-3.97 (m, 2 H),3.75-3.83 (m, 1 H), 3.40-3.70 (m, 4 H), 2.66-2.86 (m, 2 H), 2.04- 2.34(m, 5 H), 1.68-2.00 (m, 5 H), 1.36-1.55 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(5-fluoro-2- methylbenzyl)-D-prolinamide 509

LCMS-ESI (POS.) m/z: 565.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.40-7.50 (m, 2 H), 7.35- 7.40 (m, 1 H), 7.29-7.35 (m, 1 H), 4.59 (dd, J= 7.98, 2.18 Hz, 1 H), 4.42-4.57 (m, 2 H), 3.73-3.84 (m, 6 H), 3.53-3.65(m, 2 H), 2.98 (dd, J = 12.65, 10.78 Hz, 1 H), 2.67-2.84 (m, 2 H),2.30-2.47 (m, 2 H), 2.09-2.24 (m, 1 H), 1.97- 2.09 (m, 1 H), 1.86-1.95(m, 2 H), 1.77-1.85 (m, 3 H), 1.64-1.74 (m, 1 H), 1.49-1.59 (m, 1 H),0.99 (t, J = 7.41 Hz, 3 H) J 1-(((3S)-1-((3-ethyl-3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide 510

LCMS-ESI (POS.) m/z: 516.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.85- 8.97 (m, 1 H), 8.57-8.83 (m, 1 H), 7.24-8.11 (m, 4 H), 5.18-5.48(m, 1 H), 3.84-4.69 (m, 3 H), 3.61- 3.73 (m, 2 H), 3.29-3.34 (m, 3 H),1.86-2.11 (m, 1 H), 0.84-1.29 (m, 1 H), − 0.26-0.63 (m, 4 H) C(4S)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-4-fluoro-1-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-D- prolinamide 511

LCMS-ESI (POS.) m/z: 509.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.28-7.36 (m, 2 H), 7.17- 7.26 (m, 3 H), 4.96 (br t, J = 6.84 Hz, 1 H),4.50 (br d, J = 7.88 Hz, 1 H), 4.04- 4.23 (m, 5 H), 3.81 (br t, J = 7.05Hz, 1 H), 3.63- 3.74 (m, 2 H), 3.40-3.63 (m, 4 H), 3.14 (br d, J = 12.85Hz, 1 H), 2.72- 2.97 (m, 3 H), 2.38 (br s, 1 H), 2.06-2.25 (m, 2 H),2.02 (br s, 2 H), 1.73-1.97 (m, 3 H), 1.36-1.57 (m, 3 H) MN-((1R)-1-(4-chlorophenyl)ethyl)-1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2- piperazinyl)carbonyl)-D-prolinamide 512

LCMS-ESI (POS.) m/z: 510.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm9.16-9.27 (m, 1 H), 8.90- 9.02 (m, 1 H), 8.18-8.38 (m, 1 H), 7.10-7.21(m, 2 H), 6.97-7.10 (m, 1 H), 4.82-4.97 (m, 1 H), 4.21- 4.54 (m, 1 H),3.75-4.01 (m, 1 H), 3.43-3.50 (m, 1 H), 3.09-3.20 (m, 3 H), 1.78-1.90(m, 1 H), 1.68- 1.76 (m, 1 H), 1.10-1.31 (m, 1 H), 0.80-0.95 (m, 1 H),0.51-0.70 (m, 2 H), 0.34-0.47 (m, 2 H), 0.22- 0.33 (m, 1 H) C(1R,2R,5S)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-3-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide 513

LCMS-ESI (POS.) m/z: 497.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.66- 8.67 (m, 5 H), 7.62 (dd, J = 9.54, 6.16 Hz, 1 H), 7.37 (br d, J =3.24 Hz, 1 H), 4.49-5.07 (m, 2 H), 3.33- 3.38 (m, 2 H), 3.20-3.27 (m, 1H), 2.54-2.69 (m, 1 H), 1.55-1.81 (m, 2 H), 0.68- 1.41 (m, 8 H) C(1R,3R,5R)-N-((1R)-1-(4-chloro-2,5-difluorophenyl)ethyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 514

LCMS-ESI (POS.) m/z: 546.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.50- 8.61 (m, 1 H), 7.67 (d, J = 8.17 Hz, 2 H), 7.46 (br d, J = 7.79Hz, 2 H), 4.28- 4.74 (m, 3 H), 3.99-4.09 (m, 2 H), 3.88-3.96 (m, 2 H),3.70-3.85 (m, 3 H), 3.23-3.63 (m, 3 H), 2.81- 3.00 (m, 1 H), 2.04-2.29(m, 2 H), 1.81-1.98 (m, 3 H), 1.58-1.79 (m, 3 H) M(2R)-1-(1-((3-cyanoazetidin-1-yl)sulfonyl)-3-fluoropiperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide 515

LCMS-ESI (POS.) m/z: 547.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm8.58-8.70 (m, 1 H), 7.65- 7.71 (m, 1 H), 7.60-7.64 (m, 1 H), 4.61-4.81(m, 3 H), 3.96-4.17 (m, 4 H), 3.73-3.83 (m, 2 H), 3.55- 3.73 (m, 2 H),3.36-3.48 (m, 1 H), 2.93-3.05 (m, 1 H), 2.68-2.84 (m, 2 H), 2.28-2.56(m, 2 H), 2.27- 2.46 (m, 1 H), 2.10-2.23 (m, 1 H), 1.92-2.09 (m, 3 H),1.75 (br s, 2 H), 1.50- 1.63 (m, 1 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)methyl)-D- prolinamide 516

LCMS-ESI (POS.) m/z: 496.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.30- 8.72 (m, 1 H), 7.26-7.37 (m, 1 H), 7.05-7.23 (m, 2 H), 4.24-4.51(m, 3 H), 4.01-4.11 (m, 2 H), 3.89- 3.98 (m, 2 H), 3.74-3.84 (m, 1 H),3.35-3.66 (m, 4 H), 2.71-2.88 (m, 2 H), 1.87-2.33 (m, 4 H), 1.34- 1.85(m, 5 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3-difluorobenzyl)-D- prolinamide 517

LCMS-ESI (POS.) m/z: 498.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ7.23 (br t, J = 5.34 Hz, 1H), 6.74- 6.82 (m, 2H), 6.67-6.73 (m, 1H),4.62-4.87 (m, 1H), 4.42-4.54 (m, 1H), 4.30- 4.40 (m, 1H), 4.12-4.23 (m,5H), 3.97-4.06 (m, 1H), 3.84 (ddd, J = 4.20, 8.11, 10.50 Hz, 1H),3.66-3.75 (m, 2H), 3.42-3.58 (m, 3H), 3.19 (dd, J = 9.69, 12.70 Hz, 1H),3.03 (ddd, J = 3.32, 11.04, 12.39 Hz, 1H), 2.41- 2.50 (m, 1H), 2.09-2.23(m, 1H), 1.88-2.06 (m, 2H) C1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-N-(3,5-difluorobenzyl)-D- prolinamide 518

LCMS- APCI (POS.) m/z: 560.2 (M + H)⁺ 1H NMR (Methanol-d4) δ: 7.78-7.59(m, 1H), 7.58- 7.43 (m, 1H), 4.68-4.38 (m, 4H), 3.83 (d, J = 11.9 Hz,2H), 3.77-3.70 (m, 6H), 3.01-2.73 (m, 2H), 2.64 (ddd, J = 20.9, 14.6,8.6 Hz, 4H), 2.26 (dt, J = 14.8, 7.8 Hz, 2H), 2.18- 1.89 (m, 2H),1.90-1.72 (m, 2H), 1.72-1.46 (m, 4H) R methyl 3-(((S)-3-((R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)piperidin-1-yl)sulfonyl)cyclobutanecarboxylate 519

LCMS-ESI (POS.) m/z: 582.0 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm8.22-8.34 (m, 1H), 8.00- 8.14 (m, 3H), 7.68-7.78 (m, 1H), 7.42-7.51 (m,2H), 7.33-7.41 (m, 1H), 5.24 (t, J = 9.02 Hz, 1H), 5.14 (dd, J = 2.14,10.57 Hz, 1H), 3.32 (dt, J = 2.66, 6.26 Hz, 1H), 3.15-3.21 (m, 4H), 3.09(dd, J = 6.94, 9.93 Hz, 1H), 2.89 (sxt, J = 8.25 Hz, 1H), 2.77-2.80 (m,3H), 2.73 (dd, J = 2.21, 13.23 Hz, 1H), 2.34-2.45 (m, 1H), 2.18- 2.32(m, 2H), 1.73-1.81 (m, 1H), 1.00-1.06 (m, 1H), 0.89-0.98 (m, 1H) CDiasteromer #1-(1R,3R,5R)-N-((2-fluoro-4-(trifluoromethyl)phenyl)(1-methyl-5-oxopyrrolidin-3-yl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 520

LCMS-ESI (POS.) m/z: 468.2 (M + H)⁺ 1H NMR (500 MHz, METHANOL-d4) δ ppm8.27-8.36 (m, 1 H), 8.16 (s, 1 H), 7.89-8.06 (m, 2 H), 7.77-7.86 (m, 1H), 7.38-7.71 (m, 2 H), 4.19- 4.70 (m, 3 H), 4.03-4.17 (m, 2 H),3.90-4.01 (m, 2 H), 3.42-3.87 (m, 4 H), 2.37-2.48 (m, 1 H), 2.34 (s, 3H), 1.85-2.16 (m, 1 H), 1.30 (br s, 1 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((5-methyl-2-pyridinyl)methyl)-D-prolinamide 521

LCMS- APCI (POS.) m/z: 478.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.81 (d, 1 H), 7.58-7.78 (m, 3 H), 7.16-7.25 (m, 1 H), 7.06 (d, 1 H),6.53-6.66 (m, 2 H), 5.73 (s, 1 H), 4.60 (d, J = 25.1 Hz, 2 H), 3.18-3.28 (m, 1 H), 3.02-3.17 (m, 2 H), 2.12-2.25 (m, 2 H), 1.63-1.79 (m, 3H), 1.17-1.28 (m, 1 H), 1.13 (t, J = 7.1 Hz, 3 H), 0.52- 0.63 (m, 1 H),0.31-0.52 (m, 3 H). Q N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2- (ethylamino)benzoyl)-D-prolinamide522

LCMS-ESI (POS.) m/z: 551.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.42- 8.47 (m, 1 H) 8.13 (s, 1 H) 7.99-8.04 (m, 2 H) 7.77- 7.82 (m, 1 H)7.64-7.69 (m, 2 H) 7.56-7.60 (m, 2 H) 5.37 (s, 1 H) 5.05-5.13 (m, 1 H)4.92-4.99 (m, 1 H) 3.20-3.26 (m, 1 H) 1.69-2.19 (m, 6 H) 1.44- 1.69 (m,4 H) 1.06-1.17 (m, 5 H) 0.68-0.76 (m, 1 H) C(1R,3R,5R)-2-(3-(ethylsulfonyl)benzoyl)-N-((S)- (1-hydroxycyclobutyl)(4-(trifluoromethyl)phenyl)methyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide523

LCMS-ESI (POS.) m/z: 549.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.67- 8.77 (m, 1 H), 7.27-8.18 (m, 9 H), 4.55-4.67 (m, 1 H), 4.49-4.55(m, 1 H), 4.10-4.41 (m, 1 H), 3.35- 3.69 (m, 3 H), 3.28-3.30 (m, 1 H),2.12-2.25 (m, 1 H), 1.58-1.88 (m, 4 H), 1.11-1.31 (m, 2 H), 0.26- 0.67(m, 4 H) P N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzoyl)-D- prolinamide 524

LCMS-ESI (POS.) m/z: 546.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.70- 9.25 (m, 1 H), 7.17-7.56 (m, 3 H), 5.44-6.48 (m, 2 H), 4.33-4.66(m, 1 H), 3.86-4.15 (m, 4 H), 3.73- 3.85 (m, 1 H), 3.45-3.70 (m, 4 H),2.58-2.87 (m, 3 H), 2.03-2.32 (m, 1 H), 1.24-2.00 (m, 7 H) A(2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(1-(2,5-difluorophenyl)-2,2-difluoroethyl)pyrrolidine-2- carboxamide 525

LCMS-ESI (POS.) m/z: 563.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.67- 8.86 (m, 1 H), 7.99-8.09 (m, 1 H), 7.91-7.97 (m, 1 H), 7.53-7.86(m, 5 H), 4.22-5.46 (m, 2 H), 3.40- 3.66 (m, 1 H), 3.25 (br s, 3 H),2.26-2.84 (m, 3 H), 1.89-2.21 (m, 2 H), 1.19- 1.31 (m, 1 H), 0.55-0.65(m, 1 H), 0.45-0.53 (m, 1 H), 0.27-0.41 (m, 2 H) CN-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4,4-difluoro-1-(3-(methylsulfonyl)benzoyl)piperidine-2-carboxamide 526

LCMS- APCI (POS.) m/z: 514.1 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.86 (dd, J = 5.1, 55.2 Hz, 1 H), 8.63 (dd, J = 7.6, 50.4 Hz, 1 H),7.97-8.18 (m, 2 H), 7.51- 7.71 (m, 2 H), 4.52-5.05 (m, 3 H), 4.22 (t, J= 8.3 Hz, 1 H), 3.66-3.84 (m, 1 H), 3.61 (t, J = 6.6 Hz, 1 H), 1.61-1.84(m, 2 H), 0.99-1.21 (m, 2 H), 0.30- 0.59 (m, 2 H), − 0.04-0.12 (m, 1 H).Q N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-((4-(methylsulfonyl)-2-pyridinyl)carbonyl)-D- prolinamide 527

LCMS- APCI (POS.) m/z: 532.2 (M + H)⁺ 1H NMR (DMSO-d6) δ: 9.15 (s, 1H),8.78 (d, J = 8.1 Hz, 1H), 8.40-8.31 (m, 1H), 7.77-7.66 (m, 1H),7.66-7.53 (m, 2H), 5.49 (t, 1H), 4.93 (dd, J = 11.4, 3.7 Hz, 1H), 4.66(t, J = 7.7, 6.3 Hz, 1H), 4.52 (dd, J = 7.8, 6.2 Hz, 1H), 4.41 (t, J =6.1 Hz, 1H), 4.23 (t, J = 6.2 Hz, 1H), 3.50-3.35 (m, 2H), 1.80- 1.65 (m,2H), 1.28-1.08 (m, 2H), 0.85-0.67 (m, 2H) Q(1R,3R,5R)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 528

LCMS- APCI (POS.) m/z: 547.1 (M + H)⁺ 1H NMR (400 MHz, Chloroform-d) δppm 7.97 -8.10 (m, 2 H), 7.94 (s, 1 H), 7.86 (d, J = 8.5 Hz, 1 H), 7.75(dt, J = 1.4, 7.7 Hz, 1 H), 7.62 (td, J = 0.5, 7.7 Hz, 1 H), 7.33-7.43(m, 2 H), 7.28 (dd, J = 1.6, 10.4 Hz, 1 H), 5.58 (t, J = 8.4 Hz, 1 H),5.06-5.27 (m, 1 H), 4.93 (t, J = 8.3 Hz, 1 H), 4.64 (ddd, J = 6.6, 7.8,12.7 Hz, 2 H), 4.48 (t, J = 6.3 Hz, 1 H), 4.33 (t, J = 6.2 Hz, 1 H),3.71-3.77 (m, 1 H), 3.62- 3.70 (m, 2 H), 3.36-3.46 (m, 1 H), 3.03 (s, 3H), 2.68 (dddd, J = 4.0, 8.5, 14.9, 41.4 Hz, 1 H), 2.40 (ddd, J = 8.1,14.8, 22.0 Hz, 1 H), 0.71-0.85 (m, 3 H). A(4S)-4-fluoro-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 529

LCMS- APCI (POS.) m/z: 516.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 8.08- 8.27 (m, 2 H), 7.89-8.02 (m, 1 H), 7.03-7.43 (m, 2 H),5.54-5.81 (m, 2 H), 4.94-5.21 (m, 2 H), 4.61- 4.71 (m, 1 H), 4.45-4.56(m, 1 H), 4.40 (t, J = 6.2 Hz, 1 H), 3.97-4.05 (m, 1 H), 3.79-3.91 (m, 1H), 2.82-2.95 (m, 1 H), 2.66 (td, J = 6.4, 12.7 Hz, 1 H), 1.94 (ddd, J =3.4, 13.5, 37.5 Hz, 1 H), 1.63-1.83 (m, 1 H), 1.20-1.59 (m, 2 H), 1.18(td, J = 2.6, 5.4 Hz, 1 H), 0.81-0.94 (m, 1 H), 0.72-0.82 (m, 1 H),0.62-0.72 (m, 1 H). Q (1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((6-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 530

LCMS-ESI (POS.) m/z: 489.2 (M + H)⁺ 1H NMR (600 MHz, DMSO-d6) δ ppm 8.72(br d, J = 7.16 Hz, 1 H), 7.58- 7.73 (m, 3 H), 7.11-7.43 (m, 3 H),4.24-4.62 (m, 2 H), 3.41-3.64 (m, 3 H), 1.60-2.39 (m, 7 H), − 0.09- 1.36(m, 2 H) C 1-(3-cyclobutylbenzoyl)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D- prolinamide 531

LCMS-ESI (POS.) m/z: 532.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm8.15 (d, J = 1.45 Hz, 1 H), 7.95-8.09 (m, 1 H), 7.72- 7.80 (m, 1 H),7.56-7.73 (m, 2 H), 7.44-7.55 (m, 1 H), 7.38-7.44 (m, 1 H), 7.30-7.38(m, 1 H), 5.46- 6.01 (m, 2 H), 5.09-5.30 (m, 1 H), 4.88-5.01 (m, 1 H),4.53-4.73 (m, 1 H), 3.67-3.90 (m, 2 H), 2.34- 2.66 (m, 2 H), 1.18-1.32(m, 1 H), 0.46-0.66 (m, 2 H), 0.28-0.46 (m, 2 H) C(4S)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-sulfamoylbenzoyl)-D-prolinamide 532

LCMS-ESI (POS.) m/z: 562.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.59 (br t, J = 5.96 Hz, 1 H), 7.50 (s, 1 H), 7.41 (s, 1 H), 7.38 (s, 1H), 4.56-4.65 (m, 2 H), 4.31 (dd, J = 15.65, 5.29 Hz, 1 H), 4.06-4.16(m, 4 H), 3.73- 3.82 (m, 2 H), 3.54-3.64 (m, 2 H), 3.43 (tt, J = 8.66,6.58 Hz, 1 H), 2.98 (dd, J = 12.80, 11.04 Hz, 1 H), 2.66-2.81 (m, 2 H),2.43- 2.52 (m, 1 H), 2.13-2.27 (m, 1 H), 2.00-2.12 (m, 1 H), 1.86-2.00(m, 2 H), 1.78-1.86 (m, 1 H), 1.63- 1.73 (m, 1 H), 1.47-1.60 (m, 1 H) AN-(3-chloro-5-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- piperidinyl)carbonyl)-D-prolinamide533

LCMS-ESI (POS.) m/z: 518.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.60-7.64 (m, 1 H), 7.55- 7.60 (m, 1 H), 7.46-7.55 (m, 4 H), 7.40-7.45(m, 1 H), 7.32-7.38 (m, 1 H), 6.72-6.86 (m, 1 H), 5.50- 5.65 (m, 1 H),4.70-4.83 (m, 1 H), 4.50-4.65 (m, 1 H), 3.54-3.64 (m, 1 H), 3.43-3.54(m, 1 H), 2.28- 2.44 (m, 1 H), 2.02-2.19 (m, 2 H), 1.81-2.00 (m, 1 H),1.69-1.79 (m, 2 H), 1.16-1.32 (m, 3 H), 0.51- 0.69 (m, 2 H), 0.29-0.51(m, 2 H) O 1-(3-(1-carbamoylcyclopropyl)benzoyl)-N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-D-prolinamide534

LCMS-ESI (POS.) m/z: 483.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.66- 8.67 (m, 5 H), 7.50-7.66 (m, 1 H), 7.11-7.43 (m, 1 H), 4.44-5.08(m, 2 H), 3.17-3.29 (m, 4 H), 2.54- 2.68 (m, 1 H), 1.55-1.81 (m, 2 H),0.64-1.42 (m, 5 H) C (1R,3R,5R)-N-((1R)-1-(4-chloro-2,5-difluorophenyl)ethyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 535

LCMS-ESI (POS.) m/z: 587.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.57 (d, J = 8.29 Hz, 2 H), 7.39-7.46 (m, 1 H), 7.35 (d, J = 8.09 Hz, 2H), 4.89 (quin, J = 5.96 Hz, 1 H), 4.47-4.65 (m, 2 H), 4.37- 4.46 (m, 1H), 4.01-4.13 (m, 4 H), 3.78 (br d, J = 12.65 Hz, 2 H), 3.53- 3.64 (m, 2H), 2.93 (dd, J = 12.65, 11.20 Hz, 1 H), 2.64-2.80 (m, 2 H), 2.34- 2.53(m, 1 H), 2.12-2.33 (m, 2 H), 2.00-2.09 (m, 1 H), 1.76-1.95 (m, 3 H),1.44-1.71 (m, 2 H) M 1-(((3S)-1-((3-(trifluoromethoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 536

LCMS-ESI (POS.) m/z: 589.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.04- 9.09 (m, 1 H), 7.61-7.74 (m, 2 H), 7.45 (br d, J = 7.79 Hz, 2 H),4.17-4.58 (m, 4 H), 3.94 (br t, J = 5.97 Hz, 2 H), 3.50-3.74 (m, 6 H),2.60-2.86 (m, 3 H), 1.65- 2.39 (m, 7 H), 1.21-1.59 (m, 8 H), 0.78-0.97(m, 3 H) M 1-(((3S)-1-((3-(pentyloxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 537

LCMS- APCI (POS.) m/z: 538.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 8.00 (d, J = 7.9 Hz, 2 H), 7.71- 7.90 (m, 2 H), 7.63 (d, J = 8.1 Hz,2 H), 7.39-7.57 (m, 2 H), 5.09 (s, 1 H), 4.51 (d, J = 39.6 Hz, 4 H),3.88 (s, 6 H), 3.64 (d, J = 39.5 Hz, 2 H), 3.48 (s, 1 H), 3.35 (m, 1 H),0.48 (s, 4 H). V (3R)-4-((3-(5-azaspiro[2.3]hex-5-ylsulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-3-morpholinecarboxamide 538

LCMS-ESI (POS.) m/z: 526.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.82- 9.23 (m, 2 H), 8.51-8.80 (m, 1 H), 8.25-8.51 (m, 1 H), 7.76 (d, J= 6.49 Hz, 3 H), 4.66-5.03 (m, 1 H), 4.08-4.62 (m, 1 H), 3.58- 3.74 (m,1 H), 3.37-3.40 (m, 3 H), 2.55-2.73 (m, 1 H), 1.55-1.78 (m, 2 H), −0.28-1.25 (m, 7 H) C (1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 539

LCMS-ESI (POS.) m/z: 546.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.39- 8.88 (m, 1 H), 7.48-7.73 (m, 3 H), 4.22-4.49 (m, 3 H), 3.91-4.09(m, 4 H), 3.76-3.84 (m, 1 H), 3.36- 3.73 (m, 4 H), 2.70-2.91 (m, 2 H),2.61-2.69 (m, 1 H), 2.10-2.31 (m, 1 H), 1.28-1.97 (m, 7 H) C1-(((3R)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide 540

LCMS-ESI (POS.) m/z: 499.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.71* (d, J = 7.14 Hz, 1 H), 8.34 (d, J = 7.66 Hz, 1 H), 7.76- 7.81 (m,2 H), 7.43-7.49 (m, 2 H), 4.86-4.99 (m, 1 H), 4.45-4.50* (m, 1 H), 4.29(dd, J = 8.43, 4.15 Hz, 1 H), 4.03-4.09 (m, 2 H), 3.90-3.97 (m, 2 H),3.75- 3.84 (m, 1 H), 3.29-3.61 (m, 4 H), 2.71-2.87 (m, 2 H), 2.60-2.68(m, 1 H), 2.26-2.35* (m, 1 H), 2.16 -2.26* (m, 1 H), 2.02- 2.14 (m, 1H), 1.63-1.93 (m, 5 H), 1.39-1.57 (m, 2 H), 1.37* (d, J = 7.01 Hz, 3 H),1.34 (d, J = 7.01 Hz, 3 H) Spectrum appears as 3:1 mixture of rotamers,*denotes resolved minor rotamer peaks A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4- cyanophenyl)ethyl)-D-prolinamide 541

LCMS- APCI (POS.) m/z: 537.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.80 (d, J = 8.1 Hz, 1 H), 8.02 (s, 1 H), 7.71 (d, J = 10.5 Hz, 1 H),7.60 (dt, J = 8.3, 15.1 Hz, 2 H), 7.10 (s, 1 H), 5.52-5.58 (m, 1 H),5.50 (t, J = 8.8 Hz, 1 H), 4.86- 4.92 (m, 1 H), 4.73 (t, J = 5.3 Hz, 1H), 4.61-4.69 (m, 1 H), 4.52 (t, J = 7.0 Hz, 1 H), 4.42 (t, J = 6.2 Hz,1 H), 4.35 (t, J = 5.1 Hz, 1 H), 4.22 (q, J = 4.6, 5.3 Hz, 2 H), 3.59(p, J = 5.9 Hz, 2 H), 3.18-3.24 (m, 1 H), 3.09-3.15 (m, 1 H), 1.57-1.75(m, 3 H), 0.96-1.03 (m, 1 H), 0.57- 0.70 (m, 1 H). S(1R,3R,5R)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((5-((2-hydroxyethyl)amino)-2-methyl-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide 542

LCMS- APCI (POS.) m/z: 507.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 7.09- 8.34 (m, 8 H), 4.95-5.20 (m, 1 H), 3.86-4.64 (m, 8 H),3.38-3.59 (m, 1 H), 2.60-2.86 (m, 1 H), 2.14- 2.46 (m, 1 H). Q(2R)-1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-azetidinecarboxamide 543

LCMS-ESI (NEG.) m/z: 527.0 (M − H)⁻ 1H NMR (400 MHz, DMSO-d6) δ ppm 9.17(d, J = 7.26 Hz, 1 H), 8.08- 8.17 (m, 2 H), 7.94 (d, J = 7.67 Hz, 1 H),7.73- 7.79 (m, 1 H), 7.64-7.73 (m, 2 H), 7.59-7.64 (m, 1 H), 5.08 (dd, J= 8.71, 3.73 Hz, 1 H), 4.67 (t, J = 8.91 Hz, 1 H), 4.59 (t, J = 7.88 Hz,1 H), 4.14 (dd, J = 8.86, 3.68 Hz, 1 H), 3.26 (s, 3 H), 1.19-1.31 (m, 1H), 0.58-0.67 (m, 1 H), 0.45- 0.56 (m, 1 H), 0.38 (dtt, J = 12.80, 8.76,8.76, 4.48, 4.48 Hz, 2 H) C (4R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-(3-(methylsulfonyl)benzoyl)-2-oxo-1,3-oxazolidine-4- carboxamide 544

LCMS-ESI (POS.) m/z: 542.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.32(s, 1 H), 7.33-7.59 (m, 3 H), 4.23-4.52 (m, 3 H), 4.03- 4.09 (m, 2 H),3.92-3.97 (m, 2 H), 3.76-3.81 (m, 1 H), 3.30-3.70 (m, 4 H), 2.72-2.88(m, 2 H), 2.61- 2.69 (m, 1 H), 2.35-2.43 (m, 3 H), 1.63-2.23 (m, 6 H),1.31-1.56 (m, 2 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-methyl-3-(trifluoromethyl)benzyl)-D-prolinamide 545

LCMS- APCI (POS.) m/z: 521.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.85 (d, J = 7.4 Hz, 1 H), 8.05 (s, 1 H), 7.62-7.73 (m, 2 H), 7.26 (s, 1H), 4.94 (dd, J = 3.1, 11.5 Hz, 1 H), 4.68- 4.80(m, 1 H), 4.59 (t, J =8.0 Hz, 1 H), 3.52-3.62 (m, 2 H), 3.23 (s, 2 H), 3.11-3.16 (m, 1 H),2.41 (s, 2 H), 1.75 (dd, J = 3.2, 13.6 Hz, 1 H), 1.56-1.65 (m, 1 H),1.15-1.29 (m, 2 H), 0.87-0.93 (m, 1 H), 0.54-0.65 (m, 2 H), 0.43- 0.51(m, 1 H), 0.29-0.42 (m, 2 H). S(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-((2-hydroxyethyl)amino)-2-methyl-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide 546

LCMS- APCI (POS.) m/z: 529.1 (M + H)⁺ 1H NMR (400 MHz, Chloroform-d) δppm 8.08 -8.14 (m, 2 H), 7.78-7.86 (m, 2 H), 7.69-7.75 (m, 1 H), 7.64(d, J = 8.1 Hz, 2 H), 7.41 (d, J = 8.0 Hz, 2 H), 5.45 (t, J = 8.2 Hz, 1H), 5.04 (t, J = 8.3 Hz, 1 H), 4.68-4.76 (m, 2 H), 4.54 (t, J = 6.3 Hz,1 H), 4.41 (t, J = 6.3 Hz, 1 H), 3.70-3.83 (m, 4 H), 3.45 (dt, J = 6.9,14.0 Hz, 2 H), 3.12 (s, 3 H), 2.80-2.99 (m, 3 H), 2.41-2.54 (m, 2 H),1.28 (d, J = 7.0 Hz, 5 H), 0.81-0.95 (m, 2 H). A(4S)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-N-((R)-3-oxetanyl(4-(trifluoromethyl)phenyl)methyl)- D-prolinamide 547

LCMS-ESI (POS.) m/z: 545.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.97-8.16 (m, 1 H), 7.58- 7.82 (m, 1 H), 7.29-7.56 (m, 2 H), 5.33-7.15(m, 1 H), 4.35-4.65 (m, 1 H), 2.89-4.08 (m, 4 H), 2.72- 2.89 (m, 3 H),1.52-2.64 (m, 2 H), 1.13-1.47 (m, 2 H), 0.29-0.73 (m, 2 H) C(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(2,2,2-trifluoro-1-hydroxyethyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide548

LCMS-ESI (POS.) m/z: 526.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.80- 9.26 (m, 2 H), 8.53-8.75 (m, 1 H), 8.26-8.51 (m, 1 H), 7.69-7.83(m, 1 H), 7.16-7.52 (m, 2 H), 4.67- 5.03 (m, 1 H), 4.21-4.31 (m, 1 H),3.31-3.42 (m, 4 H), 2.58-2.79 (m, 1 H), 1.59-1.85 (m, 2 H), − 0.07 (s, 7H) C (1R,3R,5R)-N-((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 549

LCMS-ESI (POS.) m/z: 512.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.23- 8.74 (m, 1 H), 7.13-7.44 (m, 3 H), 4.27-4.36 (m, 3 H), 3.97-4.09(m, 2 H), 3.85-3.95 (m, 2 H), 3.73- 3.83 (m, 1 H), 3.36-3.71 (m, 4 H),2.71-2.88 (m, 2 H), 2.62-2.71 (m, 1 H), 1.65-2.30 (m, 7 H), 1.29- 1.51(m, 2 H) A N-(5-chloro-2-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 550

LCMS- APCI (POS.) m/z: 593.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.71- 8.81 (m, 1 H), 8.46 (dd, J = 7.3, 16.3 Hz, 1 H), 8.09 (ddd, J =2.4, 4.6, 8.6 Hz, 1 H), 7.87-7.97 (m, 1 H), 7.48-7.79 (m, 5 H), 4.46-4.69 (m, 3 H), 4.26-4.38 (m, 2 H), 4.16 (dd, J = 8.9, 17.1 Hz, 2 H),3.97-4.11 (m, 1 H), 3.82-3.93 (m, 1 H), 3.51-3.61 (m, 1 H), 3.11-3.31(m, 4 H), 2.13- 2.28 (m, 2 H), 1.67-1.90 (m, 4 H), 1.22 (dd, J = 4.6,8.1 Hz, 1 H), 0.96 (d, J = 6.4 Hz, 2 H), 0.85-0.93 (m, 1 H), 0.58-0.64(m, 1 H), 0.47-0.51 (m, 1 H), 0.38-0.47 (m, 2 H), 0.27- 0.36 (m, 1H),-0.02 (d, J = 49.1 Hz, 2 H). T 1-(2-(3-cyano-1-azetidinyl)-5-(methylsulfonyl)benzoyl)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D- prolinamide 551

LCMS-ESI (POS.) m/z: 485.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.60 (d, J = 8.30 Hz, 2 H), 7.41-7.53 (m, 1 H), 7.28- 7.41 (m, 2 H),4.60 (dd, J = 7.91, 1.95 Hz, 1 H), 4.39 -4.54 (m, 3 H), 4.04-4.17 (m, 5H), 3.77 (br d, J = 12.72 Hz, 2 H), 3.52- 3.66 (m, 2 H), 3.38-3.50 (m, 1H), 2.65-2.84 (m, 3 H), 2.44 (ddd, J = 9.34, 6.36, 3.24 Hz, 2 H),2.11-2.33 (m, 2 H), 1.98-2.10 (m, 2 H), 1.79-1.98 (m, 4 H), 1.66 (qt, J= 13.02, 3.96 Hz, 1 H), 1.50-1.60 (m, 1 H) C1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-cyanobenzyl)-D- prolinamide 552

LCMS-ESI (POS.) m/z: 545.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.58- 8.99 (m, 1 H), 7.56-8.08 (m, 6 H), 4.29-5.53 (m, 2 H), 3.43-3.74(m, 1 H), 2.90-3.19 (m, 2 H), 1.18- 1.35 (m, 1 H), 0.17-0.68 (m, 4 H) CN-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-4-(3-(methylsulfonyl)benzoyl)thiomorpholine-3- carboxamide 553

LCMS- APCI (POS.) m/z: 558.1 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm11.18 (s, 1 H), 8.77 (d, J = 7.3 Hz, 1 H), 7.59-7.74 (m, 4 H), 7.51-7.59(m, 1 H), 7.36- 7.45 (m, 1 H), 4.93 (dd, J = 3.5, Hz, H), (t, J = 8.0Hz, 1 H),3.18 (td, J = 2.5, 6.2 Hz, 1 H), 1.75 (dd, J = 3.4, 13.5 Hz, 1H), 1.60-1.70 (m, 1 H), 1.13- 1.27 (m, 1 H), 0.91-0.99 (m, 1 H),0.62-0.70 (m, 1 H), 0.52-0.62 (m, 1 H), 0.43-0.52 (m, 1 H), 0.29- 0.43(m, 2 H). Q (1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-(2,2,2-trifluoroacetamido)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide 554

LCMS- APCI (POS.) m/z: 557.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.30- 8.64 (m, 2 H), 7.94 (ddd, J = 2.4, 4.3, 8.9 Hz, 1 H), 7.45-7.82(m, 4 H), 7.30- 7.39 (m, 1 H), 4.61 (t, J = 7.9 Hz, 1 H), 4.49-4.54 (m,1 H), 4.11-4.37 (m, 3 H), 3.48-3.62 (m, 1 H), 3.13-3.27 (m, 3 H), 2.09-2.25 (m, 2 H), 1.66-1.82 (m, 2 H), 1.35 (dt, J = 6.9, 9.2 Hz, 2 H),1.16-1.31 (m, 2 H), 0.86-0.99 (m, 1 H), 0.26-0.65 (m, 4 H), − 0.09-0.09(m, 1 H). S N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-ethoxy-5-(methylsulfonyl)benzoyl)-D-prolinamide 555

LCMS- APCI (POS.) m/z: 476.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 8.53 (dd, J = 0.8, 5.1 Hz, 1 H), 7.70-7.76 (m, 1 H), 7.31- 7.47 (m,2 H), 7.28 (dd, J = 6.3, 9.4 Hz, 1 H), 5.19- 5.63 (m, 2 H), 4.61-4.71(m, 1 H), 4.54 (ddd, J = 4.5, 6.4, 7.9 Hz, 1 H), 4.39 (t, J = 6.1 Hz, 1H), 4.04 (dt, J = 6.1, 22.8 Hz, 1 H), 3.82 (dtd, J = 2.9, 6.0, 86.6 Hz,1 H), 3.46-3.57 (m, 1 H), 2.59-2.85 (m, 2 H), 1.93 (dd, J = 3.6, 13.5Hz, 1 H), 1.60-1.78 (m, 1 H), 1.22-1.40 (m, 3 H), 1.09- 1.17 (m, 1 H),0.83-0.92 (m, 1 H), 0.70-0.79 (m, 1 H). Q(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((4-ethyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide 556

LCMS-ESI (POS.) m/z: 533.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.53-7.68 (m, 4 H), 7.49 (br t, J = 7.40 Hz, 2 H), 7.41 (br d, J = 8.04Hz, 1 H), 7.34 (d, J = 10.38 Hz, 1 H), 5.03 (quin, J = 6.88 Hz, 1 H),4.69-4.81 (m, 1 H), 4.59 (t, J = 7.91 Hz, 1 H), 3.53- 3.67 (m, 1 H),3.39-3.53 (m, 1 H), 2.30-2.52 (m, 1 H), 1.93-2.30 (m, 10 H), 1.76-1.93(m, 1 H), 1.15- 1.33 (m, 1 H), 0.50-0.72 (m, 2 H), 0.34-0.50 (m, 2 H) C(2R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(2,2,2-trifluoro-1-hydroxyethyl)benzoyl)pyrrolidine-2- carboxamide 557

LCMS-ESI (POS.) m/z: 508.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.14- 8.61 (m, 1 H), 7.12-7.28 (m, 1 H), 6.69-6.86 (m, 2 H), 4.11-4.44(m, 3 H), 3.86-4.10 (m, 4 H), 3.69- 3.84 (m, 4 H), 3.41-3.67 (m, 4 H),2.60-2.88 (m, 3 H), 1.65-2.32 (m, 6 H), 1.31-1.57 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4- methoxybenzyl)-D-prolinamide 558

LCMS-ESI (POS.) m/z: 585.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.32- 8.67 (m, 3 H), 5.06-5.38 (m, 1 H), 4.21-4.51 (m, 1 H), 3.97-4.11(m, 2 H), 3.84-3.96 (m, 2 H), 3.74- 3.81 (m, 1 H), 3.51-3.64 (m, 3 H),3.43-3.49 (m, 1 H), 3.08-3.29 (m, 3 H), 2.69-3.04 (m, 3 H), 2.56- 2.68(m, 1 H), 1.63-2.25 (m, 7 H), 1.11-1.56 (m, 3 H) GN-((R)-3-azetidinyl(4-chloro-2,5-difluorophenyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 559

LCMS-ESI (POS.) m/z: 541.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.38- 8.62 1 H), 7.50-8.20 (m, 7 H), 5.21-5.77 (m, 1 H), 4.46-5.20 (m, 2H), 3.21-3.29 (m, 4 H), 2.52- 2.76 (m, 1 H), 1.51-1.79 (m, 2 H),0.83-1.13 (m, 1 H), 0.05-0.79 (m, 5 H) C (1R,3R,5R)-N-((S)-(2-fluoro-4-(trifluoromethyl)phenyl)(1- hydroxycyclopropyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide 560

LCMS-ESI (POS.) m/z: 526.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.96-8.03 (m, 1 H), 7.88- 7.94 (m, 1 H), 7.69-7.76 (m, 1 H), 7.57-7.62(m, 2 H), 7.19-7.45 (m, 4 H), 4.66-4.79 (m, 1 H), 4.47- 4.61 (m, 2 H),4.18-4.39 (m, 2 H), 3.54-3.67 (m, 1 H), 3.18-3.53 (m, 6 H), 2.35-2.45(m, 1 H), 1.78- 2.02 (m, 4 H) B 1-((3-(((3R)-3-hydroxy-1-pyrrolidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide, 1-((3- (((3S)-3-hydroxy-1-pyrrolidinyl)sulfonyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 561

LCMS-ESI (POS.) m/z: 558.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.11- 8.63 (m, 1 H), 7.47-7.79 (m, 4 H), 4.82-4.89 (m, 1 H), 4.39-4.54(m, 1 H), 3.74-4.13 (m, 5 H), 3.61- 3.72 (m, 1 H), 3.49-3.60 (m, 4 H),3.31-3.48 (m, 1 H), 2.58-2.90 (m, 3 H), 1.31-2.30 (m, 9 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide 562

LCMS-ESI (POS.) m/z: 569.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.60-7.68 (m, 1 H), 7.42- 7.57 (m, 3 H), 7.34 (d, J = 7.79 Hz, 2 H),7.19- 7.26 (m, 1 H), 7.14 (s, 1 H), 4.92 (quin, J = 6.81 Hz, 1 H), 4.59(br d, J = 6.75 Hz, 1 H), 4.38-4.53 (m, 2 H), 4.27-4.34 (m, 2 H), 4.08-4.15 (m, 2 H), 3.81 (br d, J = 12.20 Hz, 2 H), 3.53- 3.64 (m, 2 H), 2.97(t, J = 11.94 Hz, 1 H), 2.67- 2.81 (m, 2 H), 2.42 (ddd, J = 9.15, 6.42,3.11 Hz, 1 H), 2.10-2.33 (m, 1 H), 2.00- 2.08 (m, 2 H), 1.77-1.95 (m, 3H), 1.57-1.72 (m, 1 H), 1.50 (qd, J = 12.67, 3.50 Hz, 1 H), 1.23-1.31(m, 2 H) M 1-(((3S)-1-((3-(1H-imidazol-1-)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 563

LCMS-ESI (POS.) m/z: 549.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.46- 8.84 (m, 1 H), 7.38-8.10 (m, 5 H), 4.53-4.61 (m, 1 H), 4.27 (ddd,J = 13.07, 8.27, 4.35 Hz, 1 H), 3.50- 3.65 (m, 1 H), 3.28-3.42 (m, 4 H),2.16-2.28 (m, 1 H), 1.67-1.84 (m, 3 H), 0.88-1.21 (m, 1 H), − 0.23- 0.58(m, 4 H) C N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2,6-difluoro-3-(methylsulfonyl)benzoyl)-D-prolinamide 564

LCMS-ESI (POS.) m/z: 512.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.65(br t, J = 5.84 Hz, 1 H), 7.10- 8.03 (m, 8 H), 4.02-4.53 (m, 3 H),3.57-3.64 (m, 5 H), 3.39-3.51 (m, 1 H), 3.04-3.26 (m, 9 H), 2.20- 2.32(m, 1 H), 1.75-2.01 (m, 3 H), 0.98-1.10 (m, 6 H) C1-(3-(diethylsulfamoyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 565

LCMS-ESI (POS.) m/z: 472.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.28-7.37 (m, 2 H), 7.21- 7.27 (m, 1 H), 7.17 (d, J = 7.26 Hz, 1 H),7.12 (d, J = 7.05 Hz, 1 H), 5.47 (ddd, J = 7.96, 5.16, 2.33 Hz, 1 H),4.55 (dd, J = 8.03, 2.33 Hz, 1 H), 4.06-4.14 (m, 4 H), 3.75 (dt, J =12.41, 1.52 Hz, 2 H), 3.69 (dd, J = 14.31, 4.98 Hz, 1 H), 3.53-3.66 (m,2 H), 3.36-3.49 (m, 1 H), 2.88-3.09 (m, 2 H), 2.65-2.83 (m, 2 H), 2.38-2.57 (m, 1 H), 2.15-2.33 (m, 1 H), 2.01-2.12 (m, 1 H), 1.87-2.01 (m, 2H), 1.77-1.87 (m, 1 H), 1.64- 1.73 (m, 1 H), 1.50-1.60 (m, 1 H) AN-((7S)-bicyclo[4.2.0]octa-1,3,5-trien-7-)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide 566

LCMS-ESI (POS.) m/z: 532.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.42- 8.79 (m, 1 H), 7.89-7.96 (m, 1 H), 7.73-7.89 (m, 1 H), 7.41-7.73(m, 6 H), 4.12-4.63 (m, 2 H), 3.48- 3.63 (m, 1 H), 3.23-3.31 (m, 1 H),2.12-2.30 (m, 1 H), 1.64-1.88 (m, 3 H), 0.79-1.31 (m, 1 H), − 0.11- 0.65(m, 4 H) C N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-fluoro-5-sulfamoylbenzoyl)-D-prolinamide 567

LCMS-ESI (POS.) m/z: 519.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.62- 8.96 (m, 1 H), 7.35-7.87 (m, 5 H), 4.26-4.82 (m, 2 H), 3.79-3.88(m, 1 H), 3.57 (br d, J = 7.40 Hz, 2 H), 3.33-3.41 (m, 3 H), 1.59- 2.35(m, 5 H), 1.10-1.29 (m, 1 H), 0.15-0.65 (m, 4 H) C(2R)-N-(cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(5 -(methylsulfonyl)thiophene-2-carbonyl)pyrrolidine- 2-carboxamide 568

LCMS- APCI (NEG.) m/z: 582.2 (M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm8.05 (t, J = 1.8 Hz, 1 H), 7.90 (dt, J = 1.5, 7.9 Hz, 2 H), 7.72 (t, J =7.8 Hz, 1 H), 7.49-7.65 (m, 5 H), 4.52- 4.66 (m, 2 H), 4.46 (dd, J =5.1, 15.8 Hz, 1 H), 3.67 (dt, J = 6.9, 10.4 Hz, 1 H), 3.54 (ddd, J =4.5, 7.1, 10.3 Hz, 1 H), 2.71 (d, J = 2.2 Hz, 6 H), 2.38 (ddd, J = 5.3,8.1, 11.3 Hz, 1 H), 1.96-2.10 (m, 3 H). Q1((3-(dimethylsulfamoyl)phenyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 569

LCMS-ESI (POS.) m/z: 514.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.52- 9.06 (m, 2 H), 7.35-8.30 (m, 5 H), 4.22-5.23 (m, 2 H), 3.59-3.70(m, 2 H), 3.20-3.45 (m, 3 H), 2.09- 2.39 (m, 1 H), 1.67-1.97 (m, 3 H),1.01-1.30 (m, 1 H),-0.09-0.68 (m, 4 H) C (2R)-N-(cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(6-(methylsulfonyl)nicotinoyl)pyrrolidine-2-carboxamide 570

LCMS-ESI (POS.) m/z: 500.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.42- 8.75 (m, 1 H) 8.17 (s, 1 H) 8.06 (d, J = 7.78 Hz, 1 H) 7.66-8.03(m, 4 H) 7.41- 7.63 (m, 1 H) 4.94 (dd, J = 11.35, 3.44 Hz, 1 H) 4.49 (t,J = 7.85 Hz, 1 H) 3.24- 3.28 (m, 4 H) 1.64-1.76 (m, 2 H) 1.13-1.22 (m, 1H) 1.08 (td, J = 4.96, 2.66 Hz, 1 H) 0.67-0.78 (m, 1 H) 0.42-0.61 (m, 2H) 0.36 (br d, J = 2.08 Hz, 2 H) C (1R,3R,5R)-N-((R)-(4-cyano-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3- (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 571

LCMS-ESI (POS.) m/z: 474.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.07- 8.51 (m, 1 H), 7.10-7.22 (m, 4 H), 4.14-4.50 (m, 3 H), 4.00-4.10(m, 2 H), 3.89-3.97 (m, 2 H), 3.73- 3.83 (m, 1 H), 3.35-3.69 (m, 4 H),2.60-2.87 (m, 3 H), 2.04-2.34 (m, 4 H), 1.68-2.00 (m, 5 H), 1.35- 1.56(m, 2 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methylbenzyl)-D- prolinamide 572

LCMS-ESI (POS.) m/z: 510.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.44- 8.92 (m, 1 H), 7.43-7.91 (m, 8 H), 4.82-5.05 (m, 1 H), 4.08-4.76(m, 1 H), 3.69-3.85 (m, 1 H), 3.23- 3.57 (m, 1 H), 2.57-2.70 (m, 6 H),1.48-1.65 (m, 2 H), 1.09-1.47 (m, 3 H), 0.24-0.80 (m, 2 H) C(1R,2R,5S)-3-(3-(dimethylsulfamoyl)benzoyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide 573

LCMS- APCI (POS.) m/z: 516.1 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.89- 9.25 (m, 2 H), 8.71 (dd, J = 7.6, 86.8 Hz, 1 H), 8.22- 8.43 (m, 1H), 7.56-7.84 (m, 2 H), 5.03 (dd, J = 3.5, 11.4 Hz, 1 H), 4.59-4.83 (m,1 H), 3.74-4.20 (m, 1 H), 3.41 (dt, J = 3.1, 6.3 Hz, 4 H), 2.62-2.82 (m,1 H), 1.60-1.84 (m, 2 H), 1.08-1.39 (m, 2 H), 0.72- 1.04 (m, 2 H),0.25-0.69 (m, 3 H),-0.28-0.07 (m, 1 H). Q(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((4-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 574

LCMS-ESI (POS.) m/z: 494.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.20- 8.70 (m, 1 H), 7.39-7.49 (m, 1 H), 7.24-7.37 (m, 3 H), 4.22-4.53(m, 3 H), 4.00-4.10 (m, 2 H), 3.88- 3.98 (m, 2 H), 3.75-3.84 (m, 1 H),3.36-3.70 (m, 4 H), 2.65-2.89 (m, 2 H), 1.36-2.34 (m, 9 H) AN-(2-chlorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide 575

LCMS-ESI (POS.) m/z: 582.0 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) Shift8.33-8.38 (m, 1H), 8.10- 8.15 (m, 1H), 7.95-8.08 (m, 2H), 7.70-7.79 (m,1H), 7.43-7.50 (m, 2H), 7.34- 7.41 (m, 1H), 5.36 (dd, J = 7.85, 9.15 Hz,1H), 5.16 (dd, J = 2.40, 10.57 Hz, 1H), 3.68-3.81 (m, 1H), 3.25- 3.38(m, 2H), 3.18-3.21 (m, 3H), 2.87-2.96 (m, 1H), 2.72 (dd, J = 2.34, 13.23Hz, 1H), 2.49-2.58 (m, 3H), 2.40 (dd, J = 9.41, 17.06 Hz, 1H), 2.24-2.34(m, 1H), 2.12 (dd, J = 6.88, 17.13 Hz, 1H), 1.72-1.82 (m, 1H), 1.03-1.10(m, 1H), 0.93- 1.01 (m, 1H) C Diastereomer #2-(1R,3R,5R)-N-((2-fluoro-4-(trifluoromethyl)phenyl)(1-methyl-5-oxopyrrolidin-3-yl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 576

LCMS-ESI (POS.) m/z: 529.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.99-8.15 (m, 2 H), 7.74- 7.82 (m, 1 H), 7.53-7.74 (m, 1 H), 7.40-7.51(m, 2 H), 7.33-7.40 (m, 1 H), 6.80-7.08 (m, 1 H), 4.51 (br s, 3 H),3.32-4.21 (m, 5 H), 2.97-3.18 (m, 3 H), 1.20-1.41 (m, 1 H), 0.55- 0.75(m, 2 H), 0.36-0.53 (m, 2 H) C (3R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-(3 - (methylsulfonyl)benzoyl)-3-morpholinecarboxamide 577

LCMS- APCI (POS.) m/z: 509.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 7.37- 7.84 (m, 7 H), 5.01-5.13 (m, 2 H), 4.89-5.00 (m, 2 H),4.11-4.66 (m, 2 H), 3.46-3.74 (m, 2 H), 2.25- 2.38 (m, 1 H), 1.78-2.00(m, 3 H), 0.96-1.35 (m, 1 H),-0.04-0.74 (m, 4 H). RN-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(3-fluoro-3-oxetanyl)benzoyl)-D-prolinamide 578

LCMS-ESI (POS.) m/z: 531.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.69(d, J = 7.27 Hz, 1 H), 8.01 (dd, J = 8.69, 1.69 Hz, 1 H), 7.89 (br s, 1H), 7.55-7.81 (m, 3 H), 7.30-7.48 (m, 2 H), 6.88-7.17 (m, 1 H), 4.03-(m, 3 H), 3.31-3.48 (m, 1 H), 2.00-2.25 (m, 1 H), 1.03-1.88 (m, 6 H),0.23-0.71 (m, 4 H) C (2R)-N-((R)-cyclopropyl(4-(difluoromethyl)-2-fluorophenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2-piperidinecarboxamide 579

LCMS-ESI (POS.) m/z: 522.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.30- 8.87 (m, 1 H), 7.21-7.31 (m, 1 H), 6.91-6.99 (m, 1 H), 6.80-6.88(m, 1 H), 5.50-5.71 (m, 1 H), 4.65- 4.74 (m, 1 H), 4.02-4.42 (m, 4 H),3.90-3.97 (m, 2 H), 3.74-3.84 (m, 1 H), 3.33-3.69 (m, 4 H), 2.63- 2.89(m, 2 H), 2.14-2.33 (m, 1 H), 1.66-2.10 (m, 6 H), 1.31-1.56 (m, 2 H) A(2R)-N-(4-chloro-2,3-dihydrobenzofuran-3-)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)pyrrolidine-2-carboxamide 580

LCMS-ESI (POS.) m/z: 596.4 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.24-8.85 (m, 3H), 7.57-7.75 (m, 2H), 7.34-7.55 (m, 2H), 6.87- 6.97 (m,1H), 5.07-5.18 (m, 1H), 4.22-4.53 (m, 5H), 3.76-3.94 (m, 2H), 3.51- 3.70(m, 4H), 2.59-2.90 (m, 4H), 2.02-2.42 (m, 1H), 1.66-2.02 (m, 5H), 1.36-1.57 (m, 2H) J 1-(((3S)-1-((3-(4-pyridinyloxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 581

LCMS-ESI (POS.) m/z: 544.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.57 (d, J = 8.04 Hz, 2 H), 7.36 (d, J = 7.92 Hz, 2 H), 7.33 (br t, J =5.84 Hz, 1 H), 4.65-4.73 (m, 2 H), 4.49- 4.57 (m, 1 H), 4.40-4.46 (m, 1H), 4.06-4.16 (m, 4 H), 3.81 (br d, J = 11.03 Hz, 1 H), 3.75 (br d, J =12.72 Hz, 1 H), 3.60-3.70 (m, 2 H), 3.38-3.46 (m, 1 H), 2.93 (dd, J =12.72, 11.03 Hz, 1 H), 2.78 (td, J = 12.36, 2.66 Hz, 1 H), 2.62-2.73 (m,2 H), 2.05 (ddd, J = 13.04, 8.50, 4.02 Hz, 1 H), 1.89 (br d, J = 13.36Hz, 1 H), 1.78-1.84 (m, 1 H), 1.59-1.70 (m, 2 H), 1.49- 1.58 (m, 1 H) M(4S)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-hydroxy-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 582

LCMS-ESI (POS.) m/z: 569.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.30- 8.79 (m, 1 H), 7.84 (br s, 1 H), 7.62-7.72 (m, 2 H), 7.59 (s, 1H), 7.37-7.52 (m, 2 H), 6.30 (s, 1 H), 5.19-5.36 (m, 1 H), 4.26- 4.55(m, 4 H), 4.08-4.26 (m, 5 H), 3.42-3.81 (m, 6 H), 2.63-2.97 (m, 3 H),1.34-2.41 (m, 9 H) M 1-(((3S)-1-((3-(1H-pyrazol-1-)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 583

LCMS-ESI (POS.) m/z: 524.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.23- 8.64 (m, 1 H), 7.19-7.36 (m, 1 H), 7.03-7.12 (m, 1 H), 6.82-7.00(m, 1 H), 3.43-4.54 (m, 16 H), 2.60 -2.94 (m, 3 H), 2.05-2.36 (m, 1 H),1.35-2.04 (m, 6 H) A N-(2-chloro-3-methoxybenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- piperidinyl)carbonyl)-D-prolinamide 584

LCMS-ESI (POS.) m/z: 478.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.46- 8.70 (m, 1 H), 7.56-7.75 (m, 3 H), 7.14-7.32 (m, 1 H), 6.55-6.92(m, 3 H), 4.56-4.61 (m, 1 H), 4.30 (br dd, J = 19.40, 7.85 Hz, 1 H),3.36-3.60 (m, 2 H), 2.82-2.97 (m, 6 H), 2.06- 2.22 (m, 1 H), 1.64-1.82(m, 3 H), 1.00-1.25 (m, 1 H), 0.10-0.62 (m, 4 H)N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(3-(dimethylamino)benzoyl)-D-prolinamide 585

LCMS-ESI (POS.) m/z: 522.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.04- 8.56 (m, 1 H), 6.98 7.23 (m, 3 H), 4.76-4.98 (m, 1 H), 4.25-4.49(m, 1 H), 4.01-4.12 (m, 2 H), 3.88- 3.99 (m, 2 H), 3.74-3.86 (m, 4 H),3.47-3.68 (m, 4 H), 2.60-2.90 (m, 3 H), 2.01-2.35 (m, 1 H), 1.63- 1.98(m, 5 H), 1.23-1.56 (m, 5 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(3-fluoro-4-methoxyphenyl)ethyl)-D-prolinamide, 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(3-fluoro-4-methoxyphenyl)ethyl)-D-prolinamide 586

LCMS-ESI (POS.) m/z: 527.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.95-8.14 (m, 2 H), 7.60- 7.93 (m, 3 H), 7.46-7.58 (m, 1 H), 7.39-7.45(m, 1 H), 7.31-7.39 (m, 1 H), 3.79-4.93 (m, 3 H), 2.88- 3.19 (m, 3 H),2.50-2.73 (m, 1 H), 1.95-2.27 (m, 2 H), 1.65-1.86 (m, 1 H), 1.00-1.62(m, 4 H), 0.53- 0.73 (m, 2 H), 0.29-0.53 (m, 2 H) C(5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-5-methyl-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 587

LCMS- APCI (POS.) m/z: 527.2 (M + H)⁺ 1H NMR (Methanol-d4) δ: 7.75-7.59(m, 2H), 7.58- 7.41 (m, 2H), 4.69-4.51 (m, 1H), 4.51-4.46 (m, 1H),4.46-4.40 (m, 1H), 4.20-4.06 (m, 1H), 3.88- 3.80 (m, 1H), 3.79-3.69 (m,2H), 3.57-3.41 (m, 1H), 3.37 (s, 1H), 3.03- 2.67 (m, 7H), 2.31-2.19 (m,1H), 2.18-1.88 (m, 4H), 1.88-1.74 (m, 1H), 1.71-1.46 (m, 2H) R1-(((3S)-1-((trans-3-cyanocyclobutyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 588

LCMS-ESI (POS.) m/z: 495.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.44- 8.72 (m, 1 H), 6.51-8.11 (m, 8 H), 3.89-4.58 (m, 2 H), 3.40-3.66(m, 2 H), 3.24-3.30 (m, 3 H), 2.16- 2.33 (m, 1 H), 1.69-1.96 (m, 3 H),0.82-1.25 (m, 1 H),-0.14-0.64 (m, 4 H) A N-((R)-cyclopropyl(4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 589

(3R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide LCMS-ESI (POS.) m/z: 531.0 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.14 (s, 1 H), 8.06-8.11 (m, 1H), 7.84 (d, J = 7.66 Hz, 1 H), 7.70-7.75 (m, 1 H), 7.64-7.70 (m, 1 H),7.47-7.52 (m, 1 H), 7.41- 7.46 (m, 1 H), 7.37 (d, J = 9.99 Hz, 1 H),5.27- 5.65 (m, 1 H), 4.87-5.12 (m, 1 H), 4.37-4.65 (m, 1 H), 3.52-3.78(m, 2 H), 3.06-3.19 (m, 3 H), 2.22- 2.57 (m, 2 H), 1.13-1.36 (m, 1 H),0.63-0.75 (m, 1 H), 0.53-0.63 (m, 1 H), 0.22-0.52 (m, 2 H) C 590

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((cis-4- (trifluoromethyl)cyclohexyl)methyl)-D-LCMS-ESI (POS.) m/z: 534.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.04- 8.20 (m, 1 H), 7.64-7.77 (m, 1 H), 7.70 (br d, J = 4.25 Hz, 1 H),4.17-4.38 (m, 1 H), 3.98-4.12 (m, 2 H), 3.85-3.97 (m, 2 H), 3.73- 3.84(m, 1 H), 3.29-3.67 (m, 4 H), 3.02-3.19 (m, 1 H), 2.60-2.99 (m, 3 H),1.99-2.30 (m, 2 H), 1.80- 1.93 (m, 3 H), 0.83-1.37 (m, 3 H) Aprolinamide, 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)-D- prolinamide 591

N-(3-chloro-4-methoxybenzyl)-1-(((3S)-1-((3- LCMS-ESI (POS.) m/z: 524.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.20- 8.62 (m, 1 H), 7.26-7.32(m, 1 H), 7.14-7.19 (m, 1 H), 7.05-7.13 (m, 1 H), 4.12-4.49 (m, 3 H),4.01- 4.09 (m, 2 H), 3.89-3.98 (m, 2 H), 3.77-3.87 (m, 4 H), 3.36-3.71(m, 4 H), 2.60-2.87 (m, 3 H), 2.03- 2.29 (m, 1 H), 1.66-1.96 (m, 5 H),1.35-1.55 (m, 2 H) A cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide 592

LCMS-ESI (POS.) m/z: 506.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.01- 8.60 (m, 1 H), 6.92-7.37 (m, 3 H), 4.76-4.98 (m, 1 H), 4.23-4.52(m, 1 H), 3.42-4.13 (m, 10 H), 2.61 -2.92 (m, 3 H), 1.64-2.40 (m, 8 H),1.21-1.60 (m, 5 H) A (2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(1-(4-fluoro-3-methylphenyl)ethyl)pyrrolidine-2-carboxamide 593

(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((4-cyclopropyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS-APCI (POS.) m/z: 506.2 (M + H)⁺ 1H NMR (Methanol-d4) δ: 8.69 (d, J = 6.8Hz, 1H), 8.33 (dd, J = 5.2, 0.9 Hz, 1H), 7.38-7.31 (m, 2H), 7.30-7.23(m, 2H), 4.83 (dd, J = 11.4, 3.9 Hz, 1H), 4.33 (dd, J = 8.9, 6.9 Hz,1H), 3.09 (td, J =6.3, 2.6 Hz, 1H), 2.52 (td, J = 12.4, 6.3 Hz, 1H),2.09-1.93 (m, 1H), 1.75 (dd, J = 13.6, 3.9 Hz, 1H), 1.66-1.55 (m, 1H),1.18-1.02 (m, 1H), 1.00-0.95 (m, 1H), 0.95-0.88 (m, 2H), 0.88- 0.80 (m,2H), 0.69-0.59 (m, 1H), 0.57-0.47 (m, 1H), 0.46-0.39 (m, 1H), 0.39-0.23(m, 2H) Q 594

LCMS-ESI (POS.) m/z: 540.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.06- 8.59 (m, 1 H), 6.98-7.45 (m, 5 H), 4.24-5.05 (m, 2 H), 4.01-4.13(m, 2 H), 3.86-3.98 (m, 2 H), 3.71- 3.84 (m, 1 H), 3.46-3.67 (m, 4 H),2.60-2.92 (m, 3 H), 1.34-2.33 (m, 11 H) A(2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(1-(4-(difluoromethoxy)phenyl)ethyl)pyrrolidine-2- carboxamide 595

1-((3-(5-azaspiro[2.3]hex-5- ylsulfonyl)phenyl)carbonyl)-N-((1R)-1-(4-chlorophenyl)ethyl)-D-prolinamide LCMS- APCI (NEG.) m/z: 500.2 (M − H)1H NMR (400 MHz, Methanol-d4) δ ppm 8.12 (s, 1 H), 7.91-8.02 (m, 2 H),7.76 (q, J = 6.8, 7.3 Hz, 2 H), 7.32 (d, J = 0.8 Hz, 4 H), 4.97-5.10 (m,1 H), 4.59 (dd, J = 6.0, 8.3 Hz, 1 H), 3.89 (s, 4 H), 3.57- 3.69 (m, 1H), 3.52 (dt, J = 6.0, 10.6 Hz, 1 H), 2.28- 2.37 (m, 1 H), 1.87-1.97 (m,3 H), 1.49 (d, J = 7.0 Hz, 3 H), 0.47 (s, 4 H). A 596

LCMS-ESI (POS.) m/z: 507.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.40- 8.72 (m, 1 H) 7.89-8.21 (m, 3 H) 7.38-7.82 (m, 5 H) 3.70-5.07 (m,2 H) 3.23-3.28 (m, 4 H) 2.53- 2.61 (m, 1 H) 1.78 (dd, J = 13.56, 3.57Hz, 1 H) 1.54 -1.73 (m, 1 H) 0.65-1.19 (m, 3 H)-0.30-0.60 (m, 4 H) A(1R,3R,5R)-N-((R)-cyclopropyl(4- (trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide 597

N-((1R)-1-(2-fluoro-4- (trifluoromethyl)phenyl)ethyl)-1-(((3S)-1-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide LCMS-ESI (POS.) m/z: 565.2 (M + H)⁺1H NMR (400 MHz, CHLOROFORM-d) δ 7.50 (br d, J = 7.46 Hz, 1H), 7.37-7.46 (m, 2H), 7.31 (d, J = 10.37 Hz, 1H), 5.22 (quin, J = 7.18 Hz, 1H),4.57 (dd, J = 2.12, 8.03 Hz, 1H), 3.90 (dd, J = 5.39, 8.09 Hz, 2H),3.75-3.85 (m, 2H), 3.70-3.75 (m, 2H), 3.53- 3.66 (m, 2H), 3.04 (dd, J =10.73, 12.49 Hz, 1H), 2.70-2.88 (m, 2H), 2.30- 2.39 (m, 1H), 2.08-2.20(m, 1H), 1.96-2.08 (m, 2H), 1.81-1.90 (m, 2H), 1.62- 1.73 (m, 3H), 1.56(s, 3H), 1.45 (d, J = 6.95 Hz, 3H) A 598

(1S,3R,5S)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 544.2 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.14-9.43 (m, 2 H), 8.56- 8.72(m, 1 H), 7.41 (br d, J = 6.12 Hz, 1 H), 7.33 (dd, J = 9.48, 5.65 Hz, 1H), 7.21 (dd, J = 10.06, 5.49 Hz, 1 H), 4.76 (dd, J = 8.40, 2.80 Hz, 1H), 4.49 (dd, J = 8.55, 6.89 Hz, 1 H), 3.22-3.30 (m, 1 H), 3.18 (s, 3H), 2.76 (ddd, J = 13.61, 7.44, 2.70 Hz, 1 H), 2.01-2.17 (m, 2 H),1.20-1.33 (m, 1 H), 1.11-1.20 (m, 1 H), 0.82 (td, J = 5.08, 2.80 Hz, 1H), 0.66-0.77 (m, 1 H), 0.56-0.66 (m, 1 H), 0.40- 0.52 (m, 2 H) C 599

LCMS- APCI (POS.) m/z: 527.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 7.46- 8.01 (m, 7 H), 5.26-5.51 (m, 1 H), 4.84-5.25 (m, 4 H),4.73-4.76 (m, 1 H), 3.73-4.30 (m, 3 H), 2.66- 2.82 (m, 1 H), 2.02-2.29(m, 1 H), 1.03-1.50 (m, 1 H), − 0.05-0.89 (m, 4 H). Q(4S)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(3-fluoro-3-oxetanyl)benzoyl)-D-prolinamide 600

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((4-methyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS-APCI (POS.) m/z: 462.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) 6 ppm 8.41(d, J = 0.8, 5.0, 75.4 Hz, 1 H), 7.68 (dt, J = 0.8, 1.7, 13.4 Hz, 1 H),7.31-7.42 (m, 2 H), 7.07-7.32 (m, 2 H), 5.20-5.62 (m, 2 H), 4.95 (dd, J= 3.7, 11.4 Hz, 1 H), 4.82-4.86 (m, 1 H), 4.60-4.71 (m, 2 H), 4.50- 4.60(m, 1 H), 4.40 (t, 1 H), 4.06 (dt, J = 6.1, 14.7 Hz, 1 H), 3.82 (dtd, J= 3.0, 6.1, 86.9 Hz, 2 H), 3.46-3.57 (m, 1 H), 3.37 (s, 1 H), 2.72-2.83(m, 1 H), 2.58- 2.70 (m, 1 H), 2.46 (d, J = 16.8 Hz, 5 H), 1.89-1.99 (m,2 H), 1.69-1.78 (m, 1 H), 1.59-1.68 (m, 1 H), 1.13 (td, J = 2.6, 5.4 Hz,1 H), 0.83-0.92 (m, 1 H), 0.68-0.79 (m, 1 H). Q 601

LCMS-ESI (POS.) m/z: 529.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.27- 8.57 (m, 1 H) 7.39-8.22 (m, 7 H) 4.71-5.15 (m, 3 H) 3.59-3.91 (m,1 H) 3.23-3.28 (m, 4 H) 2.53- 2.60 (m, 1 H) 1.54-1.83 (m, 2 H) 0.47-1.13(m, 5 H) A (1R,3R,5R)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-hydroxypropyl)-2-(3-(methylsulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide 602

N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-methoxy-5- LCMS-ESI (POS.) m/z:543.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.30- 8.67 (m, 1 H), 7.96(ddd, J = 8.79, 6.58, 2.40 Hz, 1 H), 7.46-7.72 (m, 4 H), 7.29- 7.39 (m,1 H), 4.13-4.63 (m, 2 H), 3.88-3.95 (m, 3 H), 3.42-3.53 (m, 1 H),3.13-3.25 (m, 4 H), 2.10- 2.23 (m, 1 H), 1.76-1.86 (m, 1 H), 1.64-1.83(m, 3 H), 0.86-1.26 (m, 1 H), − 0.07-0.65 (m, 4 H) C(methylsulfonyl)benzoyl)-D-prolinamide 603

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((2,6-dimethyl-4-pyridinyl)carbonyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS- APCI (POS.) m/z: 476.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 7.35- 7.43 (m, 3 H), 7.27 (dd, J = 6.3, 9.4 Hz, 1 H), 5.54- 5.60 (m,1 H), 4.92 (dd, J = 4.0, 11.4 Hz, 1 H), 4.84 (dd, J = 6.5, 7.7 Hz, 1 H),4.67 (dd, J = 6.4, 7.8 Hz, 1 H), 4.60 (t, J = 6.2 Hz, 1 H), 4.38 (t, 1H), 3.46- 3.56 (m, 1 H), 3.27 (td, J = 2.6, 6.2 Hz, 1 H), 2.61- 2.70 (m,1 H), 2.54 (s, 1 H), 1.90 (dd, J = 4.0, 13.6 Hz, 1 H), 1.74-1.82 (m, 1H), 1.22 (td, J = 2.6, 5.4 Hz, 1 H), 0.80-0.88 (m, 1 H). Q 604

LCMS-ESI (POS.) m/z: 500.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.30-7.83 (m, 8 H), 4.41- 5.03 (m, 2 H), 3.22 3.77 (m, 2 H), 2.32-2.60(m, 1 H), 1.97-2.21 (m, 2 H), 1.74-1.96 (m, 3 H), 1.39- 1.54 (m, 2 H),1.16-1.27 (m, 1 H), 0.19-0.78 (m, 4 H) C1-(3-(1-cyanocyclopropyl)benzoyl)-N-((R)- cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide 605

LCMS- APCI (POS.) m/z: 498.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 8.55- 9.02 (m, 2 H), 8.02-8.13 (m, 1 H), 7.87-7.98 (m, 1 H),7.71-7.84 (m, 1 H), 7.48-7.69 (m, 2 H), 6.71- 7.07(m, 1 H), 5.10-5.17(m, 1 H), 4.63-4.70 (m, 1 H), 3.34-3.39 (m, 1 H), 2.73-2.95 (m, 1 H),1.94- 2.06 (m, 1 H), 1.72-1.93 (m, 1 H), 1.32-1.43(m, 1 H), 1.22-1.30(m,1 H), − 0.05-1.14 (m, 5 H). Q (1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(difluoromethyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 606

LCMS-ESI (POS.) m/z: 492.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.18- 8.62 (m, 1 H), 7.00-7.20 (m, 3 H), 4.18-4.50 (m, 3 H), 4.00-4.10(m, 2 H), 3.88-3.98 (m, 2 H), 3.74- 3.83 (m, 1 H), 3.34-3.68 (m, 4 H),2.61-2.86 (m, 3 H), 2.01-2.33 (m, 4 H), 1.66-1.99 (m, 5 H), 1.35- 1.56(m, 2 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-3- methylbenzyl)-D-prolinamide 607

LCMS-ESI (POS.) m/z: 492.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.88- 8.41 (m, 1 H), 7.14-7.27 (m, 1 H), 6.92-7.10 (m, 2 H), 4.17-4.47(m, 3 H), 3.99-4.10 (m, 2 H), 3.86- 3.96 (m, 2 H), 3.71-3.85 (m, 1 H),3.40-3.66 (m, 4 H), 2.60-2.88 (m, 3 H), 2.11-2.35 (m, 3 H), 1.33- 2.02(m, 8 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-6- methylbenzyl)-D-prolinamide 608

(1R,3R,5R)-2-(3-benzoylbenzoyl)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- +APCI (POS.) m/z: 535.1 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (d, J = 7.7 Hz, 1 H), 8.01 (t,J = 1.7 Hz, 1 H), 7.96 (dt, J = 1.5, 7.7 Hz, 1 H), 7.91 (dt, J = 1.4,7.8 Hz, 1 H), 7.72- 7.82 (m, 2 H), 7.67-7.75 (m, 2 H), 7.60 (q, J = 6.8,7.6 Hz, 3 H), 7.48 (dd, J = 6.3, 9.8 Hz, 1 H), 4.93 (dd, J = 3.5, 11.3Hz, 1 H), 4.48 (t, J = 8.0 Hz, 1 H), 4.35 (t, J = 5.1 Hz, 1 H), 1.70(dd, J = 3.6, 13.6 Hz, 2 H), 1.10- 1.21 (m, 1 H), 0.98-1.03 (m, 1 H),0.70 (dd, J = 5.3, 9.2 Hz, 1 H), 0.48-0.57 (m, 1 H), 0.43 (t, J = 8.8Hz, 1 H). Q 609

LCMS-ESI (POS.) m/z: 539.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.82-8.38 (m, 3 H), 7.29- 7.79 (m, 4 H), 6.54-7.22 (m, 1 H), 4.48-4.86(m, 2 H), 4.08-4.46 (m, 2 H), 2.94-3.23 (m, 3 H), 1.73- 2.60 (m, 6 H),1.17-1.37 (m, 1 H), 0.24-0.79 (m, 4 H) C N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azaspiro[3.3]heptane- 1-carboxamide 610

N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide LCMS-ESI (POS.) m/z: 559.0 (M + H)⁺1H NMR (400 MHz, CHLOROFORM-d) δ 7.29- 7.50 (m, 4H), 4.54-4.61 (m, 2H),4.43-4.54 (m, 2H), 3.99-4.06 (m, 2H), 3.72- 3.86 (m, 4H), 3.55-3.63 (m,2H) 2.96 (dd J = 10.83, 12.59 Hz, 1H), 2.66-2.83 (m, 2H), 2.36-2.45 (m,1H), 2.09-2.22 (m, 1H), 1.98- 2.09 (m, 1H), 1.85-1.95 (m, 2H), 1.77-1.85(m, 1H), 1.59-1.72 (m, 2H), 1.48- 1.59 (m, 1H) J 611

(1R,3R,5R)-2((5-cyclopropyl-3- pyridinyl)carbonyl)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 504.2 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.70 (d, J = 1.9 Hz, 1 H), 8.52(d, J = 2.2 Hz, 1 H), 7.82 (t, J = 2.1 Hz, 1 H), 7.45- 7.59 (m, 2 H),5.65 (d, J = 10.1 Hz, 1 H), 4.99 (dd, J = 4.2, 11.4 Hz, 1 H), 4.61- 4.70(m, 2 H), 4.40 (t, J = 6.1 Hz, 1 H), 3.54 (dd, J = 7.4, 14.5 Hz, 1 H),2.66 (td, J = 6.4, 12.7 Hz, 1 H), 2.08 (ddd, J = 5.0, 8.5, 13.4 Hz, 1H), 1.86-1.93 (m, 1 H), 1.74-1.86(m, 1 H), 1.09- 1.18 (m, 1 H),0.78-0.92 (m, 3 H). Q 612

(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(2-methoxy-5-(methylsulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 555.1 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.54 (s,1 H), 7.96 (dd, J = 2.5, 8.8, 15.9 Hz, 1 H), 7.53-7.71 (m, 2 H),7.32-7.48 (m, 1 H), 4.84 (dd, J = 3.1, 11.3 Hz, 1 H), 4.58 (t, J = 7.9Hz, 1 H), 4.34 (t, J = 5.1 Hz, 2 H), 3.94 (s, 2 H), 3.18 (s, 2 H), 2.98(td, J = 2.5, 6.2 Hz, 1 H), 1.74 (dd, J = 13.8, 33.6 Hz, 1 H), 1.54 (dt,J = 5.8, 11.5 Hz, 1 H), 1.12-1.23 (m, 1 H), 0.93 (td, J = 2.5, 5.1 Hz, 1H), 0.42-0.62 (m, 2 H), 0.21-0.41 (m, 2 H). Q 613

N-((6-chloro-3-pyridinyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- piperidinyl)carbonyl)-D-prolinamideLCMS-ESI (POS.) m/z: 495.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.71* (t, J = 5.77 Hz, 1 H), 8.38 (t, J = 6.03 Hz, 1 H), 8.25- 8.33 (m,1 H), 7.69 (dd, J = 8.24, 2.40 Hz, 1 H), 7.47 (d, J = 8.17 Hz, 1 H),4.20- 4.51 (m, 3 H), 4.02-4.10 (m, 2 H), 3.90-3.98 (m, 2 H), 3.76-3.83(m, 1 H), 3.29-3.69 (m, 4 H), 2.70- 2.90 (m, 2 H), 2.64 (tt, J = 11.09,3.50 Hz, 1 H), 2.23-2.30* (m, 1 H), 2.15 -2.23* (m, 1 H), 2.05- 2.13 (m,1 H), 1.63-1.96 (m, 5 H), 1.34-1.54 (m, 2 H). Spectrum appears as 2:1mixture of rotamers, *denotes resolved minor rotamer peaks. C 614

LCMS-ESI (POS.) m/z: 504.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.98- 8.42 (m, 1 H), 7.04-7.17 (m, 1 H), 6.64-6.79 (m, 2 H), 4.01-4.50(m, 5 H), 3.40-3.99 (m, 10 H), 2.56 -2.90 (m, 3 H), 2.01-2.34 (m, 4 H),1.32-1.99 (m, 7 H) A 1-(((35)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-methoxy-2- methylbenzyl)-D-prolinamide 615

(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((6-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 534.1 (M +H)⁺ 1H NMR (DMSO-d6) δ: 8.94 (d, J = 7.4 Hz, 1H), 8.75 (d, J = 8.0 Hz,1H), 8.50 (t, 1H), 8.44 (t, J = 7.8 Hz, 1H), 8.34-8.19 (m, 4H), 7.99(dd, J = 9.4, 5.8 Hz, 1H), 7.92 (dd, J = 9.4, 5.8 Hz, 1H), 7.82 (dd, J =11.1, 5.5 Hz, 1H), 7.72 (dd, J = 11.1, 5.6 Hz, 1H), 5.71 (dd, J = 11.5,2.8 Hz, 1H), 5.15 (dd, J = 11.4, 3.3 Hz, 1H), 4.76 (t, J = 7.9 Hz, 1H),4.30 (t, J = 8.5 Hz, 2H), 4.05 (td, J = 6.3, 2.5 Hz, 1H), 3.99 (td, J =6.3, 2.3 Hz, 1H), 3.03 (td, J = 12.6, 6.0 Hz, 1H), 2.11 (dd, J = 13.6,2.9 Hz, 1H), 1.95 (dd, J = 13.5, 3.4 Hz, 1H), 1.92-1.84 (m, 1H), 1.85-1.73 (m, 1H), 1.50-1.39 (m, 1H), 1.31-1.14 (m, 2H), 1.02-0.91 (m, 1H),0.89-0.78 (m, 2H), 0.78- 0.67 (m, 2H), 0.67-0.58 (m, 2H), 0.57-0.47 (m,2H), 0.25-0.12 (m, 1H), 0.04--0.05 (m, 1H) Q 616

(5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-5-methyl-1-(3-(methylsulfonyl)benzoyl)-L-prolinamide LCMS-ESI (POS.) m/z: 527.2 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.83-8.15 (m, 3 H), 7.58- 7.81(m, 2 H), 7.46-7.57 (m, 1 H), 7.39-7.46 (m, 1 H), 7.31-7.39 (m, 1 H),3.85-4.86 (m, 3 H), 2.91- 3.19 (m, 3 H), 2.49-2.71 (m, 1 H), 1.98-2.28(m, 2 H), 1.70-1.87 (m, 1 H), 0.89-1.41 (m, 4 H), 0.53- 0.73 (m, 2 H),0.30-0.52 (m, 2 H) C 617

LCMS-ESI (POS.) m/z: 483.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.28- 8.68 (m, 1 H), 7.31-8.21 (m, 6 H), 4.53-4.99 (m, 1 H), 4.21-4.40(m, 2 H), 3.24-3.38 (m, 3 H), 2.56 2.67 (m, 1 H), 1.63-2.00 (m, 2 H),0.75-1.27 (m, 5 H) C (1R,3R,5R)-N-(4-chloro-2,5-difluorobenzyl)-2-(3-(ethylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane- 3-carboxamide 618

N-(5-chloro-2-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- LCMS-ESI (POS.) m/z:508.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.22 (br t, J = 5.84 Hz,1 H), 6.92- 7.32 (m, 3 H), 4.11-4.55 (m, 3 H), 3.98-4.09 (m, 2 H),3.85-3.98 (m, 2 H), 3.73 3.85 (m, 1 H), 3.41 3.72 (m, 4 H), 3.31-3.41(m, 3 H), 2.62-2.93 (m, 3 H), 2.05-2.16 (m, 1 H), 1.61-2.00 (m, 5 H),1.23- 1.59 (m, 2 H) A prolinamide 619

LCMS-ESI (POS.) m/z: 531.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.54- 8.68 (m, 1 H), 7.21-8.18 (m, 7 H), 5.12-5.42 (m, 1 H), 4.25-4.78(m, 2 H), 3.57-4.10 (m, 2 H), 3.18- 3.29 (m, 3 H), 2.53-2.61 (m, 1 H),2.04-2.30 (m, 1 H), 1.05-1.33 (m, 1 H), 0.45-0.67 (m, 1 H), 0.03- 0.44(m, 3 H) C (4R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 620

LCMS-ESI (POS.) m/z: 501.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.22- 8.75 (m, 2H), 7.65-8.04 (m, 5H), 7.44-7.55 (m, 1H), 5.05-5.20 (m,1H), 3.98- 4.53 (m, 5H), 3.13-3.44 (m, 2H), 2.54-2.67 (m, 4H), 2.17-2.28(m, 1H), 1.22- 1.74 (m, 5H) L(2R)-N-((6-chloro-3-pyridinyl)methyl)-1-((3-((cis-3-cyanocyclobutyl)sulfonyl)phenyl)carbonyl)-2- piperidinecarboxamide,(2R)-N-((6-chloro-3- pyridinyl)methyl)-1-((3-((trans-3-cyanocyclobutyl)sulfonyl)phenyl)carbonyl)-2- piperidinecarboxamide 621

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((2-methyl-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS-APCI (POS.) m/z: 462.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.57(dd, J = 0.8, 5.2 Hz, 1 H), 7.60 (s, 1 H), 7.54 (dd, J = 0.7, 1.6, 5.2Hz, 1 H), 7.39 (dd, J = 6.1, 9.5 Hz, 1 H), 7.27 (dd, J = 6.3, 9.4 Hz, 1H), 5.57 (d, J = 10.2 Hz, 1 H), 4.94 (dd, J = 4.0, 11.4 Hz, 1 H), 4.84(dd, J = 6.5, 7.7 Hz, 1 H), 4.67 (dd, J = 6.4, 7.8 Hz, 1 H), 4.60 (t, J= 6.2 Hz, 1 H), 4.38 (t, 1 H), 3.46-3.56 (m, 1 H), 3.37 (s, 2 H), 3.28(td, J = 2.6, 6.2 Hz, 1 H), 2.63- 2.71 (m, 1 H), 2.62 (s, 3 H), 1.90(dd, J = 4.0, 13.5 Hz, 1 H), 1.74-1.82 (m, 1 H), 1.23 (td, J = 2.6, 5.3Hz, 1 H), 0.85 (dtd, J = 1.1, 5.7, 9.1 Hz, 1 H). Q 622

LCMS-ESI (POS.) m/z: 534.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.96- 8.53 (m, 1 H), 6.81-7.17 (m, 2 H), 5.15-5.32 (m, 1 H), 4.18-4.51(m, 1 H), 4.00-4.13 (m, 2 H), 3.88- 3.99 (m, 2 H), 3.74-3.87 (m, 4 H),3.44-3.72 (m, 4 H), 2.58-2.94 (m, 5 H), 2.08-2.43 (m, 2 H), 1.63- 2.06(m, 6 H), 1.30-1.57 (m, 2 H) A (2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(5-fluoro-6-methoxy-2,3-dihydro-1H-inden-1-yl)pyrrolidine-2- carboxamide 623

LCMS-ESI (POS.) m/z: 532.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.25- 8.74 (m, 1 H), 7.70-7.90 (m, 1 H), 4.18-4.51 (m, 3 H), 4.00-4.10(m, 2 H), 3.88-3.97 (m, 2 H), 3.72- 3.84 (m, 1 H), 3.36-3.65 (m, 4 H),2.57-2.86 (m, 3 H), 1.80-2.27 (m, 4 H), 1.63-1.79 (m, 2 H), 1.30- 1.57(m, 2 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3,5,6- tetrafluorobenzyl)-D-prolinamide 624

LCMS-ESI (POS.) m/z: 527.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.47- 8.77 (m, 1 H), 7.52-8.09 (m, 7 H), 4.22-4.65 (m, 2 H), 3.53-3.76(m, 1 H), 3.22-3.30 (m, 3 H), 3.01- 3.14 (m, 1 H), 2.11-2.35 (m, 1 H),1.76-1.99 (m, 2 H), 0.83-1.30 (m, 4 H), − 0.07-0.63 (m, 4 H) C(4S)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-4-methyl-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 625

LCMS-ESI (POS.) m/z: 518.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.87- 8.52 (m, 1 H), 6.77-7.31 (m, 4 H), 4.55-4.71 (m, 1 H), 4.25-4.49(m, 1 H), 3.89-4.13 (m, 4 H), 3.72 (br d, J = 2.60 Hz, 5 H), 3.43 -3.66(m, 4 H), 2.59-3.01 (m, 3 H), 1.99-2.33 (m, 1 H), 1.29-1.96 (m, 8 H),0.74-1.11 (m, 3 H) A (2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(1-(4-methoxyphenyl)propyl)pyrrolidine-2-carboxamide 626

LCMS- APCI (POS.) m/z: 545.2 (M + H)⁺ 1H NMR (Methanol-d4) δ: 7.74-7.59(m, 2H), 7.51 (t, J = 7.7 Hz, 2H), 4.63- 4.37 (m, 3H), 4.06-3.68 (m,5H), 3.27-3.21 (m, 1H), 3.00-2.73 (m, 3H), 2.71-2.54 (m, 4H), 2.51- 2.18(m, 2H), 2.19-1.87 (m, 4H), 1.88-1.79 (m, 1H), 1.72-1.41 (m, 2H) R1-(((3S)-1-((trans-3- carbamoylcyclobutyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 627

LCMS-ESI (POS.) m/z: 577.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.06- 8.48 (m, 1 H), 7.35-8.01 (m, 8 H), 4.67-4.83 (m, 1 H), 4.41-4.58(m, 1 H), 4.02 (br d, J = 4.41 Hz, 2 H), 3.82-3.89 (m, 2 H), 3.43- 3.65(m, 3 H), 2.08-2.36 (m, 1 H), 1.54-1.89 (m, 3 H), 0.51-0.96 (m, 8 H) A1-(3-((3-cyano-1-azetidinyl)sulfonyl)benzoyl)-N-((1R)-2,2-dimethyl-1-(4- (trifluoromethyl)phenyl)propyl)-D-prolinamide628

(1R,3R,5R)-N-((R)-(4-chloro-3- fluorophenyl)(cyclopropyl)methyl)-2-((5-LCMS-ESI (POS.) m/z: 492.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.83- 9.24 (m, 2 H), 8.25-8.67 (m, 2 H), 7.00-7.65 (m, 3 H), 4.96 (dd, J= 11.42, 3.63 Hz, 1 H), 4.15-4.29 (m, 1 H), 3.32-3.40 (m, 4 H),2.57-2.79 (m, 1 H), 1.56- 1.88 (m, 2 H), 0.70-1.21 (m, 3 H),-0.11 (s, 4H) C (methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 629

LCMS-ESI (POS.) m/z: 496.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.37(br d, J = 8.17 Hz, 1 H), 6.78- 7.93 (m, 7 H), 4.35-4.78 (m, 2 H),3.40-3.68 (m, 2 H), 2.50-2.67 (m, 6 H), 2.20-2.40 (m, 1 H), 1.44- 2.04(m, 5 H), 0.68-0.95 (m, 3 H) AN-((lS)-1-(4-chloro-3-fluorophenyl)propyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide 630

LCMS-ESI (POS.) m/z: 501.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.29- 8.63 (m, 1 H), 7.41-8.13 (m, 7 H), 4.64-5.09 (m, 1 H), 4.35-4.60(m, 1 H), 3.41-3.66 (m, 2 H), 3.19- 3.32 (m, 3 H), 2.14-2.33 (m, 1 H),1.89-1.96 (m, 1 H), 1.65-2.00 (m, 3 H), 1.38-1.49 (m, 1 H), 0.45- 1.02(m, 3 H) C N-((1R)-1-(2-fluoro-4- (trifluoromethyl)phenyl)propyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 631

1-(((3S)-1-((3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 519.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.53-7.66 (m, 2 H), 7.31- 7.45 (m, 3 H), 4.48-4.64 (m, 3 H), 4.37-4.47(m, 1 H), 3.99-4.08 (m, 2 H), 3.71-3.86 (m, 4 H), 3.53- 3.64 (m, 2 H),2.89-3.04 (m, 1 H), 2.64-2.83 (m, 2 H), 2.44 (ddd, J = 9.28, 6.29, 3.37Hz, 1 H), 2.10-2.33 (m, 2 H), 1.99-2.09 (m, 2 H), 1.46-1.96 (m, 8 H),1.22-1.35 (m, 1 H) M 632

LCMS-ESI (POS.) m/z: 570.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.05- 8.62 (m, 1 H), 6.75-7.21 (m, 4 H), 4.76-5.04 (m, 1 H), 4.21-4.52(m, 1 H), 3.72-4.15 (m, 8 H), 3.48- 3.67 (m, 3 H), 3.17 (br d, J = 4.28Hz, 1 H), 2.59- 2.92 (m, 3 H), 2.14-2.39 (m, 1 H), 1.96-2.14 (m, 1 H),1.64-1.93 (m, 4 H), 1.29-1.59 (m, 5 H) A(2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(1-(4- (difluoromethoxy)-3-methoxyphenyl)ethyl)pyrrolidine-2-carboxamide 633

LCMS-ESI (POS.) m/z: 522.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.09- 8.55 (m, 1 H), 6.86-7.23 (m, 3 H), 4.97-5.28 (m, 1 H), 4.26-4.54(m, 1 H), 3.88-4.13 (m, 4 H), 3.73- 3.87 (m, 4 H), 3.44-3.67 (m, 4 H),2.59-2.92 (m, 3 H), 1.23-2.35 (m, 11 H) A(2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)pyrrolidine-2-carboxamide 634

LCMS-ESI (POS.) m/z: 498.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.46(br d, J = 7.66 Hz, 1 H), 7.16- 7.97 (m, 7 H), 5.15-5.28 (m, 1 H), 4.82(br d, J = 7.27 Hz, 1 H), 4.28-4.55 (m, 1 H), 3.60 (br d, J = 6.10 Hz, 2H), 3.24-3.52 (m, 2 H), 2.57-2.71 (m, 6 H), 2.16- 2.29 (m, 1 H),1.67-1.97 (m, 3 H) A N-((1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-1-(3-(dimethylsulfamoyl)benzoyl)- D-prolinamide 635

1-((3-(5-azaspiro[2.3]hex-5- ylsulfonyl)phenyl)carbonyl)-N-((1R)-1-(3,4-dichlorophenyl)ethyl)-D-prolinamide LCMS- APCI (NEG.) m/z: 534.1 (M − H)1H NMR (400 MHz, Methanol-d4) δ ppm 8.12 (t, J = 1.7 Hz, 1 H), 7.95-8.02 (m, 2 H), 7.69-7.81 (m, 2 H), 7.45-7.52 (m, 2 H), 5.00 (p, J = 6.7Hz, 1 H), 4.59 (dd, J = 6.2, 8.2 Hz, 1 H), 3.89 (s, 4 H), 3.64 (dt, J =7.3, 10.3 Hz, 1 H), 3.45-3.56 (m, 1 H), 2.26-2.43 (m, 1 H), 1.86- 2.00(m, 3 H), 1.50 (d, J = 7.0 Hz, 3 H), 0.47 (s, 4 H). A 636

LCMS-ESI (POS.) m/z: 471.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.23- 8.59 (m, 1 H), 7.18-8.13 (m, 6 H), 4.76-5.20 (m, 1 H), 4.25-4.61(m, 1 H), 3.38-3.68 (m, 2 H), 3.22- 3.35 (m, 3 H), 2.14-2.33 (m, 1 H),1.69-2.02 (m, 3 H), 0.95-1.50 (m, 3 H) AN-((1R)-1-(4-chloro-2,5-difluorophenyl)ethyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 637

(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2- LCMS-ESI (POS.) m/z: 526.0 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.94 (br d, J = 4.67 Hz, 1 H), 8.76(br d, J = 7.40 Hz, 1 H), 7.85- 8.23 (m, 2 H), 7.52-7.77 (m, 3 H), 4.94(br dd, J = 11.42, 2.34 Hz, 1 H), 4.57 (br t, J = 7.72 Hz, 1 H),3.29-3.34 (m, 3 H), 3.28 (br s, 1 H), 2.55-2.72 (m, 1 H), 1.57-1.80 (m,2 H), − 0.21-1.28 (m, 7 H) C (methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 638

(4R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-4-hydroxy-1-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-D- prolinamide LCMS- APCI (POS.)m/z: 520.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.99- 9.13 (m, 2H), 8.42 (d, J = 2.2 Hz, 1 H), 7.25-7.45 (m, 2 H), 5.63 (d, J = 10.3 Hz,1 H), 4.57-4.77 (m, 3 H), 4.41-4.50 (m, 1 H), 4.36 (p, J = 5.3 Hz, 1 H),3.75 (dd, J = 5.4, 10.4 Hz, 1 H), 3.55 (td, J = 5.3, 10.4 Hz, 2 H),2.45-2.62 (m, 1 H), 1.93 (dt, J = 5.6, 12.9 Hz, 1 H). Q 639

(2R)-1-(4-((3-cyanoazetidin-1-yl)sulfonyl)-1-methylpiperazine-2-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide LCMS-ESI (POS.) m/z:543.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.48 (br d, J = 5.19 Hz,1 H), 7.58- 7.76 (m, 2 H), 7.47 (br dd, J = 12.13, 8.11 Hz, 2 H),4.24-4.56 (m, 3 H), 4.02- 4.16 (m, 2 H), 3.89-4.00 (m, 2 H), 3.68-3.84(m, 2 H), 3.55-3.67 (m, 1 H), 3.46-3.54 (m, 1 H), 3.35- 3.46 (m, 2 H),2.81-3.12 (m, 4 H), 2.62-3.21 (m, 5 H), 2.36-2.37 (m, 1 H), 2.22-2.33(m, 1 H), 2.07- 2.14 (m, 1 H), 1.88-2.05 (m, 2 H), 1.70-1.83 (m, 1 H) M640

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-ethyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS- APCI(POS.) m/z: 460.2 (M + H)⁺ 1H NMR (DMSO-d6) δ: 8.67 (d, J = 7.7 Hz, 1H),8.63 (d, J = 5.0, 0.8 Hz, 1H), 8.51 (d, J = 8.1 Hz, 1H), 8.47 (d, J =5.0, 0.8 Hz, 1H), 7.75 (dd, J = 9.5, 6.2 Hz, 1H), 7.72-7.66 (m, 3H),7.61 (dd, J = 9.8, 6.3 Hz, 1H), 7.56-7.47 (m, 2H), 7.44 (dd, J = 5.0,1.8 Hz, 1H), 5.58 (dd, J = 11.6, 2.8 Hz, 1H), 4.99 (dd, J = 11.4, 3.1Hz, 1H), 4.63 (t, J = 8.0 Hz, 1H), 4.26 (t, J = 8.4 Hz, 2H), 4.08 (td, J= 6.3, 2.6 Hz, 1H), 3.92 (td, J = 6.2, 2.5 Hz, 1H), 2.91- 2.70 (m, 4H),2.00-1.78 (m, 3H), 1.76-1.57 (m, 2H), 1.44-1.24 (m, 6H), 1.20-1.04 (m,2H), 0.95- 0.77 (m, 2H), 0.74-0.63 (m, 2H), 0.61-0.52 (m, 1H), 0.52-0.36(m, 3H), 0.15--0.05 (m, 2H) Q 641

(4R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-4-hydroxy-1-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-D- prolinamide LCMS- APCI(POS.) m/z: 504.1 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 9.27 (dd, 1H), 9.12 (dd, J = 1.9, 70.9 Hz, 1 H), 8.74 (dd, J = 7.7, 45.9 Hz, 1 H),8.44 (d, J = 44.7 Hz, 1 H), 7.77 (ddd, J = 6.2, 9.4, 12.8 Hz, 1 H), 7.62(ddd, J = 6.3, 9.9, 44.8 Hz, 1 H), 5.33 (dd, J = 5.4, 84.1 Hz, 1 H),4.59-4.71 (m, 1 H), 4.44 (dq, J = 5.8, 33.1 Hz, 1 H), 3.98-4.24 (m, 1H), 3.70 (ddd, J = 6.0, 10.0, 101.4 Hz, 1 H), 1.86 (dt, J = 6.4, 12.7Hz, 1 H), 1.31-1.44 (m, 1 H), 1.04-1.16(m, 1 H),0.70 (dt, J = 8.7, 36.1Hz, 1 H), 0.55 (s, 1 H), 0.44-0.52 (m, 1 H), − 0.05-0.24 (m, 1 H). Q 642

LCMS-ESI (POS.) m/z: 492.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.19- 8.59 (m, 1 H), 6.99-7.16 (m, 3 H), 4.15-4.51 (m, 3 H), 3.99-4.09(m, 2 H), 3.87-3.97 (m, 2 H), 3.74- 3.83 (m, 1 H), 3.33-3.70 (m, 4 H),2.62-2.86 (m, 3 H), 2.03-2.34 (m, 4 H), 1.67-1.99 (m, 5 H), 1.36- 1.56(m, 2 H) Q 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-5- methylbenzyl)-D-prolinamide 643

LCMS-ESI (POS.) m/z: 474.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.18- 8.63 (m, 1 H), 6.96-7.25 (m, 4 H), 4.14-4.50 (m, 3 H), 3.97-4.09(m, 2 H), 3.86-3.96 (m, 2 H), 3.74- 3.83 (m, 1 H), 3.33-3.71 (m, 4 H),2.62-2.92 (m, 2 H), 2.26-2.29 (m, 3 H), 1.86-2.12 (m, 4 H), 1.66- 1.84(m, 3 H), 1.36-1.53 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-methylbenzyl)-D- prolinamide 644

1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-D- prolinamide LCMS- APCI (NEG.)m/z: 520.1 (M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm 8.74 (d, J = 5.3Hz, 1 H), 8.14 (t, J = 1.8 Hz, 1 H), 8.00 (ddt, J = 1.3, 3.2, 7.9 Hz, 2H), 7.73-7.85 (m, 2 H), 7.53- 7.62 (m, 1 H), 4.57-4.71 (m, 3 H), 4.11(td, J = 1.2, 8.6 Hz, 2 H), 3.92 (ddq, J = 3.3, 6.4, 9.6 Hz, 2 H), 3.69(dt, J = 6.9, 10.2 Hz, 1 H), 3.56-3.64 (m, 1 H), 3.44- 3.56 (m, 1 H),2.36-2.44 (m, 1 H), 2.01-2.09 (m, 2 H), 1.89-2.00 (m, OH). A 645

LCMS-ESI (POS.) m/z: 567.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) 68.29-8.79 (m, 1H), 7.22-8.12 (m, 5H), 4.00-4.58 (m, 7H), 3.37- 3.72 (m,6H), 2.61-2.79 (m, 2H), 1.63-2.43 (m, 6H), 1.29-1.60 (m, 2H) J1-(((3S)-1-((1,1-dioxido-3-thietanyl)sulfamo)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 646

LCMS- APCI (POS.) m/z: 557.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.76 (dd, J = 7.2, 18.8 Hz, 1 H), 7.93 -7.99 (m, 1 H), 7.55-7.78 (m, 4H), 7.30-7.39 (m, 1 H), 5.21 (dd, 1 H), 4.47- 4.57 (m, 1 H), 4.35-4.48(m, 1 H), 3.92 (s, 4 H), 3.11-3.25 (m, 4 H), 2.81- 3.11 (m, 2 H), 2.18(t, J = 13.4 Hz, 2 H), 1.41-1.72 (m, 4 H), 1.01-1.40 (m, 5 H), 0.24-0.68(m, 6 H). C (2R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-methoxy-5-(methylsulfonyl)benzoyl)-2-piperidinecarboxamide 647

(1R,3R,5R)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((2-(2-methyl-2-propanyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 520.2 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.64 (dd, J = 0.9, 5.0 Hz, 1 H),7.82 (dd, J = 0.9, 1.5 Hz, 1 H), 7.54-7.59 (m, 2 H), 7.49-7.54 (m, 2 H),5.66 (d, J = 10.1 Hz, 1 H), 4.97 (dd, J = 4.1, 11.4 Hz, 1 H), 4.86-4.89(m, 5 H), 4.62- 4.70 (m, 2 H), 4.37-4.43 (m, 1 H), 3.52-3.62 (m, 1 H),3.27 (td, J = 2.6, 6.2 Hz, 1 H), 2.61-2.71 (m, 1 H), 1.86-1.94 (m, 1 H),1.74-1.83 (m, 1 H), 1.24 (td, J = 2.6, 5.3 Hz, 1 H), 0.81-0.89 (m, 1 H).A 648

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-pyrrolidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 514.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm8.75* (t, J = 5.96 Hz, 1 H), 8.43 (t, J = 6.04 Hz, 1 H), 7.60- 7.73 (m,2 H), 7.46 (br d, J = 7.98 Hz, 2 H), 4.53* (dd, J = 8.45, 2.64 Hz, 1 H),4.26 -4.44 (m, 3 H), 4.04-4.14 (m, 2 H), 3.92-4.01 (m, 2 H), 3.72-3.86(m, 1 H), 3.19-3.68 (m, 7 H), 2.94* (quin, J = 7.54 Hz, 1 H), 2.06-2.26(m, 2 H), 1.72- 2.04 (m, 4 H) Spectrum appears as 3:1 mxiture ofrotamers, *denotes resolved minor rotamer peaks M 649

LCMS-ESI (POS.) m/z: 500.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.69- 8.72 (m, 1 H), 7.11-8.05 (m, 8 H), 4.09-4.56 (m, 3 H), 3.69-3.80(m, 3 H), 3.44-3.68 (m, 6 H), 3.43- 3.66 (m, 6 H), 3.13 (br d, J = 3.63Hz, 2 H), 2.68- 2.85 (m, 3 H), 2.17-2.37 (m, 1 H), 1.76-2.02 (m, 3 H),1.23 (br s, 6 H) C 1-(3-(methoxy(methyl)sulfamoyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 650

(1S,3R,5S)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-2-azabicyc1o[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 510.0 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.18-9.39 (m, 2 H), 8.56- 8.68(m, 1 H), 7.29-7.37 (m, 1 H), 7.11-7.20 (m, 2 H), 4.74 (dd, J = 8.40,2.80 Hz, 1 H), 4.48 (t, J = 7.83 Hz, 1 H), 3.21-3.29 (m, 1 H), 3.14-3.20(m, 3 H), 2.75 (ddd, J = 13.53, 7.46, 2.44 Hz, 1 H), 2.00-2.15 (m, 2 H),1.19-1.31 (m, 1 H), 1.10-1.19 (m, 1 H), 0.80 (td, J = 5.00, 2.64 Hz, 1H), 0.63-0.73 (m, 1 H), 0.54-0.63 (m, 1 H), 0.35- 0.51 (m, 2 H) C 651

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,5-dichlorobenzyl)-D- prolinamide LCMS-ESI(POS.) m/z: 528.2 (M + H)⁺ additional 1H count due to H2O overlap 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.50 (br t, J = 5.96 Hz, 1 H), 7.30 (s, 1H), 7.26 (d, J = 2.38 Hz, 1 H), 7.16- 7.21 (m, 1 H), 4.64 (dd, J = 7.98,1.97 Hz, 1 H), 4.58 (dd, J = 15.86, 6.84 Hz, 1 H), 4.37 (dd, J = 15.86,5.49 Hz, 1 H), 4.06-4.16 (m, 4 H), 3.78 (ddt, J = 12.63, 3.90, 2.05,2.05 Hz, 2 H), 3.53-3.65 (m, 2 H), 3.43 (tt, J = 8.66, 6.58 Hz, 1 H),3.00 (dd, J = 12.75, 10.99 Hz, 1 H), 2.67-2.82 (m, 2 H), 2.43-2.52 (m, 1H), 2.12-2.26 (m, 1 H), 1.95- 2.11 (m, 2 H), 1.79-1.95 (m, 2 H),1.53-1.73 (m,3 H) A 652

LCMS-ESI (POS.) m/z: 546.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.32- 8.77 (m, 1 H), 7.33-7.65 (m, 3 H), 4.29-4.55 (m, 3 H), 4.00-4.11(m, 2 H), 3.89-3.99 (m, 2 H), 3.75- 3.84 (m, 1 H), 3.35-3.70 (m, 4 H),2.65-2.90 (m, 2 H), 2.05-2.34 (m, 2 H), 1.68-2.02 (m, 5 H), 1.36- 1.55(m, 2 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-D-prolinamide 653

LCMS-ESI (POS.) m/z: 561.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.83 (br s, 1 H), 7.70 (br d, J = 7.01 Hz, 1 H), 7.31- 7.55 (m, 5 H),7.14 (br d, J = 5.71 Hz, 1 H), 5.22 (br s, 1 H), 4.57 (br t, J = 7.40Hz, 1 H), 3.36-3.77 (m, 6 H), 2.99-3.25 (m, 1 H), 2.25 (br d, J = 13.75Hz, 1 H), 1.18-2.03 (m, 17 H), 0.54 -0.83 (m, 2 H) N(2R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-((1,1-dioxido-2,3-dihydro-1-benzothiophen-6-yl)carbonyl)-2- piperidinecarboxamide 654

(R)-1-((S)-1-(1-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide LCMS-ESI (POS.) m/z:545.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.57 (d, J = 8.09 Hz,2H), 7.42- 7.51 (m, 1H), 7.36 (d, J = 7.98 Hz, 2H), 4.61 (dd, J = 2.02,8.03 Hz, 1H), 4.38- 4.56 (m, 4H), 4.07-4.12 (m, 2H), 3.96-4.03 (m, 2H),3.75-3.83 (m, 2H), 3.56- 3.62 (m, 2H), 2.83-2.96 (m, 3H), 2.66-2.78 (m,2H), 2.41-2.50 (m, 1H), 2.12- 2.24 (m, 1H), 2.00-2.10 (m, 1H), 1.83-1.94(m, 2H), 1.75-1.82 (m, 1H), 1.59- 1.66 (m, 1H), 1.44-1.56 (m, 1H) J 655

LCMS- APCI (NEG.) m/z: 520.1 (M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm6.86 (t, J = 1.8 Hz, 1 H), 6.68- 6.76 (m, 3 H), 6.49-6.57 (m, 1 H), 6.46(d, J = 8.1 Hz, 1 H), 6.38 (d, J = 7.7 Hz, 1 H), 3.33-3.45 (m, 2 H),3.28 (d, J = 16.6 Hz, 1 H), 2.83 (t, J = 8.6 Hz, 2 H), 2.65 (ddd, J =4.1, 6.3, 8.7 Hz, 2 H), 2.37-2.46 (m, 1 H), 2.19-2.34 (m, 2 H),1.04-1.16 (m, 1 H), 0.74-0.86 (m, 2 H), 0.58- 0.71 (m, 1 H). A1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-((6-(trifluoromethyl)-2-pyridinyl)methyl)-D- prolinamide 656

(4S)-N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-4-(difluoromethyl)-1-(3-(methylsulfonyl)benzoyl)-D- prolinamide LCMS-ESI(POS.) m/z: 563.2 (M + H)⁺ Note: cyclopropyl methyne obscured by non-specific grease 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.11 (s, 1 H), 8.09(br d, J = 7.91 Hz, 1 H), 7.81 (d, J = 7.79 Hz, 1 H), 7.68- 7.76 (m, 1H), 7.55 (br d, J = 7.01 Hz, 1 H), 7.45- 7.51 (m, 1 H), 7.41-7.44 (m, 1H), 7.36 (br d, J = 9.99 Hz, 1 H), 5.59-5.96 (m, 1 H), 4.90 (dd, J =8.37, 3.57 Hz, 1 H), 4.57 (t, J = 7.98 Hz, 1 H), 3.72 (dd, J = 10.96,7.98 Hz, 1 H), 3.52 (dd, J = 11.09, 6.16 Hz, 1 H), 3.06-3.15 (m, 3 H),2.91-3.04 (m, 1 H), 2.52- 2.69 (m, 1 H), 2.08 (dt, J = 13.36, 8.17 Hz, 1H), 1.06-1.12 (m, 1 H), 0.61- 0.69 (m, 1 H), 0.51-0.61 (m, 1 H),0.36-0.50 (m, 2 H) C 657

LCMS-ESI (POS.) m/z: 556.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.39- 8.91 (m, 1 H), 7.49-7.71 (m, 2 H), 7.00-7.08 (m, 1 H), 5.49-5.65(m, 1 H), 4.75-4.83 (m, 1 H), 4.17- 4.49 (m, 2 H), 4.00-4.09 (m, 2 H),3.88-3.97 (m, 2 H), 3.74-3.83 (m, 1 H), 3.33-3.68 (m, 4 H), 2.64- 2.85(m, 2 H), 2.13-2.42 (m, 1 H), 1.64-2.12 (m, 6 H), 1.30-1.56 (m, 2 H) A(2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(5-(trifluoromethyl)-2,3-dihydrobenzofuran-3- yl)pyrrolidine-2-carboxamide658

(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((4-methyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS- APCI(POS.) m/z: 480.2 (M + H)⁺ 1H NMR (DMSO-d6) δ: 8.70 (d, J = 7.5 Hz, 1H),8.59-8.51 (m, 2H), 8.38 (d, J = 5.0, 0.7 Hz, 1H), 7.80 (ddd, J = 21.6,9.4, 5.9 Hz, 2H), 7.71-7.62 (m, 2H), 7.62-7.53 (m, 2H), 7.41 (d, J =5.0, 1.8, 0.9 Hz, 1H), 7.35 (d, J = 5.0, 1.7, 0.9 Hz, 1H), 5.54 (dd, J =11.5, 2.8 Hz, 1H), 4.95 (dd, J = 11.4, 3.2 Hz, 1H), 4.60 (t, J = 7.9 Hz,1H), 4.24 (t, J = 8.4 Hz, 1H), 4.02 (td, J = 6.3, 2.5 Hz, 1H), 3.94-3.81(m, 1H), 2.84-2.66 (m, 1H), 2.44 (d, J = 12.9 Hz, 6H), 1.89 (dd, J =13.4, 2.8 Hz, 1H), 1.79 (dd, J = 13.4, 3.2 Hz, 1H), 1.73-1.63 (m, 1H),1.63-1.53 (m, 1H), 1.33- 1.20 (m, 2H), 1.17-1.07 (m, 1H), 1.07-0.96 (m,1H), 0.83-0.74 (m, 2H), 0.69-0.59 (m, 2H), 0.59- 0.52 (m, 1H), 0.50-0.36(m, 4H), 0.19-0.06 (m, 1H), 0.03-− 0.05 (m, 1H) Q 659

LCMS-ESI (POS.) m/z: 546.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.02- 8.44 (m, 1 H), 7.54-7.65 (m, 3 H), 4.47-4.57 (m, 1 H), 4.22-4.45(m, 2 H), 4.01-4.10 (m, 2 H), 3.88- 3.97 (m, 2 H), 3.74-3.84 (m, 1 H),3.38-3.63 (m, 4 H), 2.70-2.85 (m, 2 H), 1.93-2.31 (m, 2 H), 1.66- 1.93(m, 5 H), 1.32-1.57 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-6-(trifluoromethyl)benzyl)-D-prolinamide 660

N-(2-chloro-5-methylbenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide LCMS-ESI(POS.) m/z: 508.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.17- 8.66(m, 1 H), 7.02-7.36 (m, 3 H), 4.14-4.43 (m, 3 H), 4.00-4.09 (m, 2 H),3.86-3.99 (m, 2 H), 3.75- 3.87 (m, 1 H), 3.25-3.71 (m, 4 H), 2.72-2.91(m, 2 H), 2.62-2.72 (m, 1 H), 2.28-2.37 (m, 1 H), 2.23- 2.31 (m, 3 H),1.66-2.16 (m, 6 H), 1.33-1.58 (m, 2 H) A 661

(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((4-ethyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS- APCI(POS.) m/z: 494.2 (M + H)⁺ 1H NMR (DMSO-d6) δ: 8.72 (d, J = 7.4 Hz, 1H),8.59 (d, J = 5.0, 0.8 Hz, 1H), 8.56 (d, J = 7.9 Hz, 1H), 8.43 (d, J =5.0, 0.8 Hz, 1H), 7.87-7.75 (m, 2H), 7.71-7.62 (m, 3H), 7.58 (dd, J =11.0, 5.5 Hz, 1H), 7.46 (dd, J = 5.0, 1.8 Hz, 1H), 7.41 (dd, J = 5.1,1.8 Hz, 1H), 5.55 (dd, J = 11.5, 2.7 Hz, 1H), 4.96 (dd, J = 11.4, 3.2Hz, 1H), 4.61 (t, J = 8.0 Hz, 1H), 4.25 (t, J = 8.4 Hz, 1H), 4.05 (td, J= 6.3, 2.5 Hz, 1H), 3.89 (td, J = 6.1, 2.8 Hz, 1H), 2.87- 2.69 (m, 4H),1.90 (dd, J = 13.4, 2.9 Hz, 1H), 1.86- 1.77 (m, 2H), 1.76-1.64 (m, 1H),1.64-1.55 (m, 1H), 1.28 (q, J = 8.3, 7.6 Hz, 6H), 1.17-1.08 (m, 1H),1.08-1.02 (m, 1H), 0.86-0.75 (m, 2H), 0.71- 0.62 (m, 2H), 0.62-0.53 (m,1H), 0.52-0.35 (m, 4H), 0.17-0.08 (m, 1H), 0.06-− 0.08 (m, 1H) C 662

LCMS-ESI (POS.) m/z: 514.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.22- 9.20 (m, 4 H), 7.48-7.77 (m, 3 H), 4.12-4.63 (m, 2 H), 3.53 (brdd, J = 14.99, 7.20 Hz, 2 H), 3.39 (br d, J = 10.51 Hz, 3 H), 2.12- 2.32(m, 1 H), 1.67-1.92 (m, 3 H), 0.86-1.29 (m, 1 H),-0.14-0.64 (m, 4 H) CN-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D- prolinamide 663

N-(4-chloro-3-fluorobenzyl)-1-(((3S)-1-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide LCMS-ESI (POS.) m/z: 517.2 (M + H)⁺1H NMR (400 MHz, CHLOROFORM-d) δ 7.38- 7.46 (m, 1H), 7.33 (t, J = 7.83Hz, 1H), 7.03 (dd, J = 1.87, 9.85 Hz, 1H), 6.94- 7.00 (m, 1H), 4.59 (dd,J = 2.18, 7.98 Hz, 1H), 4.43- 4.52 (m, 1H), 4.30 (dd, J = 5.49, 15.45Hz, 1H), 3.88 (dd, J = 2.33, 8.14 Hz, 2H), 3.67-3.84 (m, 4H), 3.56- 3.65(m, 2H), 2.99 (dd, J = 10.68, 12.65 Hz, 1H), 2.68-2.85 (m, 2H), 2.40-2.48 (m, 1H), 2.13-2.25 (m, 1H), 2.01-2.10 (m, 1H), 1.79-1.96 (m, 3H),1.63- 1.71 (m, 2H), 1.55 (s, 3H) A 664

1-(((3S)-1-(3-oxetanylsulfonyl)-3- piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS- APCI (POS.) m/z: 504.1 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 7.63 (d, J = 8.0 Hz, 2 H), 7.50(d, J = 7.9 Hz, 2 H), 4.90- 4.95 (m, 2 H), 4.83-4.88 (m, 2 H), 4.63-4.74(m, 1 H), 4.38-4.52 (m, 3 H), 3.73-3.87 (m, 4 H), 2.73- 2.85 (m, 2 H),2.19-2.33 (m, 1 H), 1.91-2.16 (m, 5 H), 1.79-1.86 (m, 1 H), 1.54-1.66(m, 2 H). R 665

LCMS-ESI (POS.) m/z: 526.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.80- 8.99 (m, 1 H), 8.51-8.79 (m, 1 H), 7.67-8.18 (m, 2 H), 7.62-8.26(m, 3 H), 7.20-7.54 (m, 2 H), 4.71- 5.03 (m, 1 H), 3.87-4.30 (m, 1 H),3.14-3.38 (m, 4 H), 2.57-2.82 (m, 1 H), 1.57-1.88 (m, 2 H), − 0.31- 1.19(m, 7 H) C (1R,3R,5R)-N-((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 666

N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-methyl-5-(methylsulfonyl)benzoyl)-D-prolinamide LCMS- APCI (POS.) m/z: 527.2 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (d, J = 7.5 Hz, 1 H), 7.86 (dd,J = 2.1, 8.0 Hz, 1 H), 7.49- 7.74 (m, 6 H), 4.55-4.65 (m, 2 H), 4.35 (t,J = 5.1 Hz, 1 H), 4.09-4.29 (m, 3 H), 3.50-3.64 (m, 2 H), 3.23 (d, J =1.5 Hz, 3 H), 3.13 (t, J = 6.5 Hz, 2 H), 2.37 (s, 2 H), 2.31 (s, 1 H),1.65-1.80 (m, 4 H), 1.18- 1.26 (m, 1 H), 0.43-0.51 (m, 1 H), 0.40 (d, J= 4.9 Hz, 1 H), 0.31 (d, J = 8.2 Hz, 1 H). Q 667

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((6-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 500.1 (M +H)⁺ 1H NMR (DMSO-d6) δ: 8.63 (d, J = 7.7 Hz, 1H), 8.44 (d, J = 8.1 Hz,1H), 8.28 (t, J = 7.9, 0.7 Hz, 1H), 8.21 (t, J = 7.9, 0.7 Hz, 1H),8.09-8.02 (m, 2H), 8.01-7.97 (m, 2H), 7.63 (dd, J = 9.4, 6.2 Hz, 1H),7.57 (dd, J = 9.4, 6.2 Hz, 1H), 7.50 (dd, J = 9.9, 6.3 Hz, 1H), 7.41(dd, J = 9.9, 6.4 Hz, 1H), 5.47 (dd, J = 11.6, 2.8 Hz, 1H), 4.91 (dd, J= 11.4, 3.3 Hz, 1H), 4.51 (t, J = 7.9 Hz, 1H), 4.04 (t, J = 8.5 Hz, 1H),3.81 (td, J = 6.3, 2.5 Hz, 1H), 3.74 (td, J = 6.3, 2.3 Hz, 1H), 2.80(td, J = 12.6, 5.8 Hz, 1H), 1.86 (dd, J = 13.6, 2.9 Hz, 1H), 1.74- 1.63(m, 2H), 1.62-1.53 (m, 1H), 1.29-1.13(m, 3H), 1.08-0.99 (m, 1H),0.99-0.89 (m, 1H), 0.65- 0.58 (m, 1H), 0.57-0.51 (m, 2H), 0.49-0.40 (m,1H), 0.39-0.32 (m, 2H), 0.31-0.19 (m, 2H), − 0.06 -− 0.17 (m, 1H), −0.22- − 0.34 (m, 1H) Q 668

(2R)-1-((S)-1-((3-hydroxy-3-methylazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(1-(4-(trifluoromethyl)phenyl)propyl)pyrrolidine-2- LCMS-ESI (POS.) m/z: 561.2(M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.50- 7.70 (m, 3H), 7.30-7.45(m, 2H), 4.75-4.90 (m, 1H), 4.54-4.72 (m, 1H), 3.68- 3.97 (m, 6H),3.47-3.67 (m, 2H), 2.95-3.09 (m, 1H), 2.63-2.87 (m, 2H), 2.33- 2.52 (m,1H), 2.08-2.23 (m, 1H), 1.93-2.07 (m, 2H), 1.62-1.88 (m, 7H), 1.53- 1.60(m, 3H), 0.83-0.98 (m, 3H) A carboxamide 669

LCMS-ESI (POS.) m/z: 573.1 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ7.30- 7.68 (m, 4H), 4.30-4.83 (m, 3H), 3.41-4.07 (m, 8H), 2.92-3.08 (m,1H), 2.65- 2.92 (m, 2H), 2.31-2.65 (m, 2H), 2.01-2.26 (m, 2H), 1.75-1.95(m, 3H), 1.47- 1.67 (m, 5H) JN-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide 670

(2S)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-methyl-1-(3-(methylsulfonyl)benzoyl)-2-azetidinecarboxamide LCMS-ESI (POS.) m/z:531.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.97 (br d, J = 7.01Hz, 1 H), 8.17-8.32 (m, 1 H), 8.11 (d, J = 7.78 Hz, 1 H), 7.93 (d, J =7.66 Hz, 1 H), 7.72 (t, J = 7.85 Hz, 1 H), 7.33 (dd, J = 9.28, 5.64 Hz,1 H), 7.24 (dd, J = 10.12, 5.45 Hz, 1 H), 4.54-4.60 (m, 1 H), 4.24 (td,J = 9.28, 5.58 Hz, 1 H), 4.16 (td, J = 8.95, 7.01 Hz, 1 H), 3.12 (s, 3H), 2.96-3.04 (m, 1 H), 2.12 (ddd, J = 11.94, 9.28, 5.51 Hz, 1 H), 1.87(s, 3 H), 1.16-1.31 (m, 1 H), 0.62- 0.69 (m, 1 H), 0.53-0.62 (m, 1 H),0.39-0.48 (m, 2 H) C 671

2-(3-((3-cyanoazetidin-1-yesulfonyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide LCMS-ESI (POS.) m/z: 583.2 (M + H)⁺1H NMR (500 MHz, DMSO-d6) δ ppm 8.58 (br s, 1 H), 7.94-8.06 (m, 2 H),7.89-7.94 (m, 1 H), 7.78-7.89 (m, 1 H), 7.53 (br d, J = 7.75 Hz, 1 H),7.46 (br d, J = 6.62 Hz, 1 H), 7.28 -7.37 (m, 1 H), 7.25 (br s, 1 H),7.19 (br d, J = 9.60 Hz, 1 H), 7.01-7.15 (m, 2 H), 6.83-7.00 (m, 1 H),5.02 (br s, 1 H), 4.56 (br s, 1 H), 4.34-4.48 (m, 1 H), 4.23- 4.33 (m, 1H), 4.14-4.23 (m, 1 H), 4.05-4.13 (m, 1 H), 4.02 (br s, 1 H), 3.81- 3.95(m, 2 H), 3.57-3.78 (m, 1 H), 3.21-3.28 (m, 1 H), 3.17 (s, 1 H) I 672

LCMS-ESI (POS.) m/z: 504.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.02- 8.55 (m, 1 H), 6.75-7.21 (m, 3 H), 3.88-4.50 (m, 7 H), 3.70-3.85(m, 4 H), 3.40-3.68 (m, 4 H), 2.60- 2.92 (m, 3 H), 2.10-2.33 (m, 4 H),1.66-2.08 (m, 5 H), 1.32-1.57 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-methoxy-3- methylbenzyl)-D-prolinamide 673

LCMS- APCI (POS.) m/z: 547.1 (M + H)⁺ 1H NMR (DMSO-d6) δ: 9.18 (d, J =9.0 Hz, 1H), 8.09-7.99 (m, 2H), 7.80- 7.66 (m, 3H), 5.93 (dd, J = 25.9,9.0 Hz, 1H), 4.84- 4.65 (m, 2H), 4.65-4.54 (m, 2H), 3.59 (t, J = 6.6 Hz,1H), 3.56-3.40 (m, 3H), 3.28 (d, J = 10.7 Hz, 2H), 1.96-1.66 (m, 4H),1.06 (t, J = 7.0 Hz, 2H) A N-((S)-(3-fluoro-3-oxetanyl)(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 674

LCMS-ESI (POS.) m/z: 546.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.38- 8.76 (m, 1 H), 7.60-7.75 (m, 2 H), 7.37-7.46 (m, 1 H), 4.26-4.55(m, 3 H), 3.98-4.10 (m, 2 H), 3.87- 3.97 (m, 2 H), 3.74-3.84 (m, 1 H),3.40-3.69 (m, 4 H), 2.59-2.90 (m, 3 H), 2.05-2.33 (m, 1 H), 1.65- 1.99(m, 5 H), 1.33-1.56 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-5-(trifluoromethyl)benzyl)-D-prolinamide 675

LCMS-ESI (POS.) m/z: 514.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.44- 9.01 (m, 2 H), 7.42-8.10 (m, 5 H), 4.12-4.65 (m, 2 H), 3.51-3.61(m, 2 H), 3.32 (br d, J = 11.68 Hz, 3 H), 2.12-2.30 (m, 1 H), 1.61-1.95(m, 3 H), 0.87- 1.32 (m, 1 H), − 0.11-0.68 (m, 4 H) CN-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-D- prolinamide 676

(1R,3R,5R)-N-((S)-(3-fluoro-3-oxetanyl)(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3- (methylsulfonyl)benzoyl)-2-LCMS- APCI (POS.) m/z: 559.1 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm9.21 (d, J = 8.9 Hz, 1 H), 8.20 (t, J = 1.8 Hz, 1 H), 7.99-8.10 (m, 2H), 7.74-7.83 (m, 2 H), 7.70 (s, 2 H), 5.87 (dd, J = 8.9, 25.5 Hz, 1 H),5.02 (dd, J = 3.9, 11.4 Hz, 1 H), 4.53-4.74 (m, 3 H), 4.35 (t, J = 5.1Hz, 1 H), 3.28 (s, 3 H), 1.73 (dd, J = 4.2, 13.6 Hz, 2 H), 1.17-1.23 (m,1 H), 0.76-0.83 (m, 1 H). A azabicyclo[3.1.0]hexane-3-carboxamide 677

LCMS- APCI (NEG.) m/z: 496.2 (M − H) 1H NMR (400 MHz, DMSO-d6) δ ppm8.25 (s, 1 H), 7.79-7.87 (m, 1 H), 7.74-7.79 (m, 1 H), 7.62- 7.74 (m, 4H), 7.50 (d, J = 8.1 Hz, 2 H), 4.80 (s, 1 H), 4.44 (d, J = 5.2 Hz, 2 H),3.82 (s, 1 H), 3.24 (s, 1 H), 2.70 (s, 5 H), 2.21 (d, J = 13.8 Hz, 1 H),1.62-1.78 (m, 3 H), 1.47 (t, J = 10.1 Hz, 2 H). Q1-(3-(N,N-dimethylsulfamoyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamide 678

LCMS-ESI (POS.) m/z: 514.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.48(d, J = 7.66 Hz, 1 H), 7.38- 7.96 (m, 8 H), 4.63-4.97 (m, 1 H),4.35-4.60 (m, 1 H), 3.52-3.75 (m, 4 H), 3.27-3.51 (m, 2 H), 2.59- 2.70(m, 6 H), 2.15-2.31 (m, 1 H), 1.64-1.90 (m, 3 H) A1-(3-(dimethylsulfamoyl)benzoyl)-N-((1S)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D- prolinamide 679

LCMS-ESI (POS.) m/z: 570.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.00- 8.78 (m, 3 H), 7.56-7.78 (m, 2 H), 7.35-7.56 (m, 2 H), 5.41 (br d,J = 6.75 Hz, 1 H), 3.96-4.66 (m, 8 H), 3.51-3.79 (m, 4 H), 2.61- 3.02(m, 3 H), 1.30-2.42 (m, 9 H) M 1-(((3S)-1-((3-(1H-1,2,4-triazol-1-)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 680

LCMS- APCI (POS.) m/z: 516.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 8.98- 9.39 (m, 2 H), 8.33-8.73 (m, 1 H), 7.49-7.88 (m, 3 H),5.17-5.25 (m, 1 H), 4.65-4.76 (m, 1 H), 3.44- 3.52 (m, 1 H), 2.77-3.03(m, 1 H), 2.00-2.10 (m, 1 H), 1.78-1.99 (m, 1 H), 1.37-1.48 (m, 1 H),1.28- 1.35 (m, 1 H), 0.93-1.18 (m, 1 H),-0.06-0.87 (m, 4 H). Q(1R,3R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-(trifluoromethyl)-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 681

LCMS-ESI (POS.) m/z: 508.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.24- 8.72 (m, 1 H), 6.54-6.85 (m, 3 H), 3.91-4.56 (m, 7 H), 3.71-3.85(m, 4 H), 3.43-3.70 (m, 4 H), 2.61- 2.95 (m, 3 H), 1.66-2.33 (m, 6 H),1.28-1.62 (m, 2 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-5- methoxybenzyl)-D-prolinamide 682

(4R)-N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-4-(difluoromethyl)-1-((5-(methylsulfonyl)-3-pyridinyl)carbonyl)-D-prolinamide LCMS-ESI (POS.) m/z: 564.0 (M + H)⁺Note: cyclopropyl methyne obscured by non- specific grease 1H NMR (500MHz, CHLOROFORM-d) δ ppm 9.24-9.30 (m, 1 H), 9.05 (d, J = 1.69 Hz, 1 H),8.41 (t, J = 1.95 Hz, 1 H), 7.45- 7.52 (m, 1 H), 7.40-7.45 (m, 1 H),7.31-7.39 (m, 2 H), 5.63-5.98 (m, 1 H), 4.88 (dd, J = 8.37, 3.70 Hz, 1H), 4.41-4.65 (m, 1 H), 3.78 (dd, J = 10.77, 7.91 Hz, 1 H), 3.51-3.63(m, 1 H), 3.17-3.21 (m, 3 H), 2.94- 3.08 (m, 1 H), 2.50-2.59 (m, 1 H),2.08-2.19 (m, 1 H), 1.28-1.34 (m, 1 H), 0.62-0.70 (m, 1 H), 0.54- 0.62(m, 1 H), 0.46 (dq, J = 9.55, 4.73 Hz, 1 H), 0.36 -0.43 (m, 1 H) C 683

(4S)-4-fluoro-1-(((3S)-1-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 551.0 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.54- 7.66 (m, 2H), 7.35-7.45 (m,2H), 7.29-7.35 (m, 1H), 5.18-5.48 (m, 1H), 4.72 (t, J = 7.83 Hz, 1H),4.37-4.60 (m, 2H), 4.01 (dd, J = 12.49, 19.44 Hz, 1H), 3.84-3.91 (m,2H), 3.59-3.84 (m, 5H), 2.95 (dd, J = 10.63, 12.80 Hz, 1H), 2.60-2.85(m, 4H), 2.30-2.50 (m, 1H), 1.76-1.91 (m, 2H), 1.50- 1.75 (m, 6H) J 684

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluorobenzyl)-D- prolinamide LCMS-ESI (POS.)m/z: 478.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.23-7.34 (m, 4H), 7.09- 7.15 (m, 1 H), 7.03-7.09 (m, 1 H), 4.61 (br d, J = 7.53 Hz, 1H), 4.42-4.55 (m, 2 H), 4.10-4.17 (m, 4 H), 3.78 (br d, J = 12.33 Hz, 2H), 3.53-3.66 (m, 2 H), 3.41-3.51 (m, 1 H), 3.00 (br t, J = 11.74 Hz, 1H), 2.69-2.83 (m, 2 H), 2.44 (br s, 1 H), 2.15-2.25 (m, 1 H), 1.51-2.12(m, 5 H) A 685

Diastereomer #3 (1R,3R,5R)-N-((2-fluoro-4-(trifluoromethyl)phenyl)(5-oxopyrrolidin-3-yl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 568.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.30-8.43 (m, 1H), 8.12 (br d,J = 7.92 Hz, 1H), 8.07 (d, J = 7.79 Hz, 1H), 7.87 (br d, J = 8.95 Hz,1H), 7.75 (t, J = 7.85 Hz, 1H), 7.43-7.50 (m, 2H), 7.38 (d, J = 10.38Hz, 1H), 5.29-5.42 (m, 2H), 5.13 (dd, J = 2.21, 10.64 Hz, 1H), 3.38 (t,J = 9.15 Hz, 1H), 3.28-3.34 (m, 1H), 3.20-3.24 (m, 1H), 3.19 (s, 3H),2.98-3.08 (m, 1H), 2.69 (br d, J = 12.72 Hz, 1H), 2.28-2.39 (m, 2H),2.09 (dd, J = 6.68, 17.19 Hz, 1H), 1.70-1.82 (m, 1H), 1.04-1.11 (m, 1H),0.93-1.00 (m, 1H) C 686

(1R,3R,5R)-N-((R)-cyclopropyl(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(cyclopropylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 552.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.95 (d, J = 4.93 Hz, 1 H),8.26-8.37 (m, 1 H), 7.78- 7.91 (m, 1 H), 7.64-7.68 (m, 1 H), 7.56-7.68(m, 1 H), 7.37-7.49 (m, 1 H), 7.18-7.28 (m, 2 H), 5.10- 5.15 (m, 1 H),4.33-4.47 (m, 1 H), 3.20-3.28 (m, 1 H H), 2.87-2.92 (m, 1 H), 2.62-2.70(m, 1 H), 2.33- 2.47 (m, 1 H), 1.77-1.90 (m, 1 H), 1.39-1.50 (m, 2 H),1.10-1.26 (m, 4 H), 0.91-1.00 (m, 1 H), 0.58- 0.74 (m, 2 H), 0.35-0.51(m, 2 H) H 687

LCMS-ESI (POS.) m/z: 548.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.40- 8.88 (m, 1 H), 7.42-7.91 (m, 8 H), 4.09-4.64 (m, 2 H), 3.48-3.66(m, 1 H), 3.09-3.24 (m, 1 H), 2.11- 2.28 (m, 1 H), 1.62-1.89 (m, 3 H),0.85-1.28 (m, 1 H), 0.00-0.65 (m, 4 H) C1-(2-chloro-5-sulfamoylbenzoyl)-N-((R)- cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide 688

LCMS-ESI (POS.) m/z: 585.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.30- 8.77 (m, 1 H), 7.59-7.75 (m, 2 H), 7.45 (br d, J = 7.01 Hz, 2 H),4.27-4.57 (m, 3 H), 4.14-4.27 (m, 3 H), 4.03 (br d, J = 3.63 Hz, 2 H),3.50-3.79 (m, 4 H), 2.60- 2.91 (m, 3 H), 2.31-2.44 (m, 3 H), 1.69-2.17(m, 6 H), 1.36-1.63 (m, 2 H) M1-(((3S)-1-((3-(3-methyl-1,2,4-oxadiazol-5-)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 689

LCMS- APCI (POS.) m/z: 525.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 7.63- 8.15 (m, 6 H), 6.56-6.60 (m, 1 H), 3.49-4.53 (m, 12 H),1.83-2.34 (m, 4 H). A 1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)-D- prolinamide 690

LCMS-ESI (POS.) m/z: 531.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.47- 8.80 (m, 1 H), 7.49-8.03 (m, 6 H), 4.30-4.32 (m, 1 H), 4.25-4.62(m, 1 H), 3.44-3.61 (m, 2 H), 3.33- 3.41 (m, 3 H), 2.14-2.30 (m, 1 H),1.65-1.88 (m, 3 H), 0.93-1.26 (m, 1 H), − 0.08-0.64 (m, 4 H) CN-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(4-fluoro-3-(methylsulfonyl)benzoyl)-D-prolinamide 691

LCMS- APCI (POS.) m/z: 505.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 7.18- 8.95 (m, 7 H), 4.90-4.95 (m, 2 H), 4.06-4.63 (m, 4 H),3.39-3.68 (m, 2 H), 2.17-2.32 (m, 1 H), 1.73- 1.94 (m, 3 H), 1.66 (s, 3H), 0.93-1.29 (m, 1 H), − 0.06-0.67 (m, 4 H). QN-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(3-methyl-3-oxetanyl)benzoyl)-D-prolinamide 692

LCMS-ESI (POS.) m/z: 590.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.25- 8.86 (m, 2 H), 7.45 (br d, J = 7.79 Hz, 2 H), 7.36- 7.77 (m, 2 H),6.97-7.30 (m, 1 H), 4.25-4.61 (m, 4 H), 3.88-4.09 (m, 10 H), 3.83-3.88(m, 2 H), 3.41- 3.69 (m, 4 H), 3.17 (s, 1 H), 2.58-2.91 (m, 3 H),1.58-2.41 (m, 7 H), 1.31- 1.57 (m, 2 H) M1-(((3S)-1-((3-((methoxyacetyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 693

(4R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-methyl-3-(3-(methylsulfonyl)benzoyl)-2-oxo-4- imidazolidinecarboxamide LCMS-ESI(POS.) m/z: 542.0 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.19 (s,1 H), 8.10 (d, J = 7.91 Hz, 1 H), 7.89 (d, J = 7.78 Hz, 1 H), 7.65 (t, J= 7.79 Hz, 1 H), 7.39- 7.51 (m, 2 H), 7.36 (d, J = 10.38 Hz, 1 H), 7.29(br s, 1 H), 4.97 (dd, J = 9.34, 4.02 Hz, 1 H), 4.53 (t, J = 8.17 Hz, 1H), 3.83 (dd, J = 9.47, 4.02 Hz, 1 H), 3.62 (t, J = 9.41 Hz, 1 H), 3.10(s, 3 H), 2.87 (s, 3 H), 1.21- 1.35 (m, 1 H), 0.61-0.73 (m, 1 H),0.52-0.60 (m, 1 H), 0.46 (dq, J = 9.70, 4.90 Hz, 1 H), 0.36-0.42 (m, 1H) C 694

LCMS-ESI (POS.) m/z: 496.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.37- 8.81 (m, 1 H), 7.02-7.16 (m, 1 H), 6.96 (br d, J = 7.40 Hz, 2 H),4.19-4.48 (m, 3 H), 3.99-4.10 (m, 2 H), 3.89-3.97 (m, 2 H), 3.75- 3.84(m, 1 H), 3.35-3.72 (m, 4 H), 2.71-2.86 (m, 2 H), 2.60-2.69 (m, 1 H),2.07-2.33 (m, 1 H), 1.69- 1.98 (m, 5 H), 1.32-1.59 (m, 2 H) M1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,5-difluorobenzyl)-L- prolinamide 695

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-2-((5-methyl-3-pyridinyl)carbonyl)-2-azabicyc1o[3.1.0]hexane-3- carboxamide LCMS-APCI (POS.) m/z: 462.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.75(d, J = 2.0 Hz, 1 H), 8.53 (d, 1 H), 8.03 (td, J = 0.9, 2.0 Hz, 1 H),7.39 (dd, J = 6.1, 9.5 Hz, 1 H), 7.27 (dd, J = 6.3, 9.4 Hz, 1 H), 5.57(d, J = 10.2 Hz, 1 H), 4.98 (dd, J = 4.2, 11.4 Hz, 1 H), 4.84 (dd, J =6.5, 7.7 Hz, 1 H), 4.67 (dd, J = 6.4, 7.9 Hz, 1 H), 4.60 (t, J = 6.2 Hz,1 H), 4.37 (t, 1 H), 4.12 (q, J = 7.1 Hz, 1 H), 3.45- 3.56 (m, 1 H),2.67 (dddd, J = 1.1, 6.4, 11.6, 13.3 Hz, 1 H), 2.45 (s, 3 H), 2.03 (s, 1H), 1.90 (dd, J = 4.2, 13.5 Hz, 1 H), 1.75-1.85 (m, 1 H), 1.21-1.29 (m,2 H), 0.89 (dtd, J = 1.1, 5.7, 9.2 Hz, 1 H). Q 696

N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-methyl-3-(3-(methylsulfonyl)benzoyl)-2-oxoimidazolidine-4- carboxamide LCMS-ESI(POS.) m/z: 542.2 (M + H)⁺ Note: Amide 1H obscured by solevent 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 8.19 (s, 1 H), 8.07-8.14 (m, 1 H),7.76-7.93 (m, 1 H), 7.61-7.70 (m, 1 H), 7.40-7.52 (m, 2 H), 7.31- 7.40(m, 2 H), 4.93-5.13 (m, 1 H), 4.44-4.58 (m, 1 H), 3.81-4.02 (m, 1 H),3.57-3.68 (m, 1 H), 3.06- 3.15 (m, 3 H), 2.83-2.90 (m, 3 H), 1.22-1.35(m, 1 H), 0.53-0.72 (m, 2 H), 0.33-0.51 (m, 2 H) C 697

LCMS-ESI (POS.) m/z: 613.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.27-8.76 (m, 1H), 7.58-7.75 (m, 2H), 7.27-7.57 (m, 6H), 5.00- 5.20 (m,1H), 4.19-4.48 (m, 3H), 3.77-3.93 (m, 1H), 3.34-3.75 (m, 6H), 2.53- 2.73(m, 2H), 2.02-2.34 (m, 3H), 1.53-2.02 (m, 5H), 1.13-1.44 (m, 2H) J(2R)-1-((3S)-1-((2-(4-chlorophenyl)azetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide 698

LCMS-ESI (POS.) m/z: 558.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.21_ 8.64 (m, 1 H), 7.01-7.51 (m, 4 H), 5.01-5.19 (m, 1 H), 4.25-4.49 (m, 1H), 4.01-4.14 (m, 2 H), 3.88- 4.00 (m, 2 H), 3.74-3.85 (m, 1 H),3.47-3.66 (m, 4 H), 2.59-2.91 (m, 3 H), 1.99-2.36 (m, 1 H), 1.61- 1.97(m, 5 H), 1.23-1.58 (m, 5 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-(difluoromethoxy)-4-fluorophenyl)ethyl)-D- prolinamide 699

1-(((3S)-1-((3-(4-chlorobenzyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 627.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.56 (d, J = 8.04 Hz, 2 H),7.47 (br s, 1 H), 7.35 (d, J = 8.04 Hz, 2 H), 7.25- 7.28 (m, 2 H), 7.07(d, J = 8.56 Hz, 2 H), 4.60 (dd, J = 7.91, 1.69 Hz, 1 H), 4.38-4.55 (m,2 H), 3.88 (t, J = 7.66 Hz, 2 H), 3.73- 3.82 (m, 2 H), 3.54-3.66 (m, 4H), 2.78-2.93 (m, 4 H), 2.62-2.78 (m, 2 H), 2.42-2.56 (m, 1 H), 2.10-2.32 (m, 1 H), 2.00-2.09 (m, 1 H), 1.81-1.98 (m, 3 H), 1.73-1.81 (m, 1H), 1.58-1.69 (m, 3 H), 1.44- 1.58 (m, 2 H) M 700

1- (((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(5-fluoro-2- methoxybenzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 508.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.12- 8.56 (m, 1 H), 6.82-7.17 (m, 3 H), 4.29-4.59 (m, 1 H), 4.12-4.29(m, 2 H), 3.87-4.11 (m, 4 H), 3.74- 3.84 (m, 4 H), 3.49-3.71 (m, 4 H),2.62-2.89 (m, 3 H), 2.03-2.26 (m, 1 H), 1.63-1.99 (m, 5 H), 1.32- 1.57(m, 2 H) A 701

1-(3-cyanobenzoyl)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide LCMS-ESI (POS.) m/z:460.0 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.82-7.88 (m, 1 H),7.74- 7.81 (m, 2 H), 7.56-7.64 (m, 1 H), 7.49 (br dd, J = 16.53, 7.83Hz, 2 H), 7.39-7.44 (m, 1 H), 7.34 (br d, J = 10.37 Hz, 1 H), 4.70-4.80(m, 1 H), 4.60 (t, J = 7.88 Hz, 1 H), 3.52- 3.63 (m, 1 H), 3.38-3.49 (m,1 H), 2.34-2.47 (m, 1 H), 2.00-2.18 (m, 2 H), 1.83-1.97 (m, 1 H), 1.20-1.34 (m, 1 H), 0.50-0.69 (m, 2 H), 0.31-0.50 (m, 2 H) C 702

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-methyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS-APCI (POS.) m/z: 446.1 (M + H)⁺ 1H NMR (DMSO-d6) δ: 8.66 (d, J = 7.8 Hz,1H), 8.59 (d, J = 5.0 Hz, 1H), 8.50 (d, J = 8.1 Hz, 1H), 8.43 (d, J =5.1 Hz, 1H), 7.78-7.63 (m, 2H), 7.60 (dd, J = 9.8, 6.3 Hz, 1H), 7.52(dd, J = 9.9, 6.4 Hz, 1H), 7.46 (d, 1H), 7.40 (d, J = 4.9 Hz, 1H), 5.57(dd, J = 11.5, 2.7 Hz, 1H), 4.97 (dd, J = 11.4, 3.2 Hz, 1H), 4.62 (t, J= 8.0 Hz, 1H), 4.25 (t, J = 8.4 Hz, 2H), 4.05 (td, J = 6.3, 2.5 Hz, 1H),3.90 (td, J = 6.1, 2.7 Hz, 1H), 3.79- 3.65 (m, 2H), 2.48 (d, J = 13.3Hz, 5H), 2.01-1.76 (m, 4H), 1.75-1.67 (m, 1H), 1.66-1.57 (m, 1H),1.38-1.20 (m, 3H), 1.16- 1.04 (m, 2H), 0.89-0.77 (m, 2H), 0.73-0.60 (m,2H), 0.60-0.51 (m, 1H), 0.50-0.39 (m, 3H), 0.16- 0.05 (m, 1H) Q 703

1-(((3S)-1-((3,3-difluoro-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamideLCMS-ESI (POS.) m/z: 539.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.57 (d, J = 8.04 Hz, 1 H), 7.35 (d, J = 8.04 Hz, 3 H), 4.37-4.64 (m, 3H), 3.80 (br d, J = 12.46 Hz, 2 H), 3.53-3.65 (m, 2 H), 2.96 (dd, J =12.33, 11.29 Hz, 1 H), 2.67-2.81 (m, 2 H), 2.45 (ddd, J = 12.26, 6.16,3.11 Hz, 1 H), 2.13-2.26 (m, 1 H), 2.00-2.11 (m, 1 H), 1.77-1.95 (m, 3H), 1.66 (qt, J = 13.04, 3.80 Hz, 1 H), 1.50 (qd, J = 12.72, 3.89 Hz, 1H), 1.19-1.38 (m, 2 H) M 704

LCMS- APCI (POS.) m/z: 568.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 7.09- 7.50 (m, 7 H), 4.24-4.45 (m, 2 H), 4.11 (dd, J = 7.0, 9.4 Hz,2 H), 3.68-3.87 (m, 3 H), 3.27-3.54 (m, 2 H), 2.79-2.83 (m, 3 H),2.06-2.17 (m, 1H), 1.60- 1.78 (m, 3 H), 0.79-1.16 (m, 1 H),-0.22-0.56(m, 4 H). Q N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(1-(methylsulfonyl)-3-azetidinyl)benzoyl)-D- prolinamide 705

LCMS-ESI (POS.) m/z: 472.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.38- 8.94 (m, 1 H), 7.05-7.36 (m, 4 H), 5.13-5.44 (m, 1 H), 4.20-4.45(m, 1 H), 3.72-4.16 (m, 5 H), 3.49- 3.71 (m, 4 H), 2.90-3.07 (m, 1 H),2.59-2.89 (m, 3 H), 2.16-2.38 (m, 1 H), 1.66-2.12 (m, 6 H), 1.33- 1.57(m, 2 H) A (2R)-N-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)pyrrolidine-2-carboxamide 706

(4S)-4-fluoro-N-((S)-(3-fluoro-3-oxetanyl)(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3- LCMS- APCI (POS.) m/z:565.1 (M + H)⁺ 1H NMR (DMSO-d6) δ: 9.33 (d, J = 8.9 Hz, 1H), 8.05-8.01(m, 1H), 7.96- 7.87 (m, 1H), 7.84-7.65 (m, 4H), 5.94 (dd, J = 26.1, 9.0Hz, 1H), 5.38 (s, 1H), 5.25 (s, 1H), 4.86-4.51 (m, 4H), 4.07-3.86 (m,2H), 3.62 (dd, J = 19.6, 12.5 Hz, 1H), 3.45 (qd, J = 7.0, 5.1 Hz, 2H),1.11- 1.00 (m, 3H) C (methylsulfonyl)benzoyl)-D-prolinamide 707

LCMS-ESI (POS.) m/z: 580.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.30- 8.78 (m, 2 H), 7.60-7.85 (m, 3 H), 7.24-7.51 (m, 4 H), 4.24-4.55(m, 4 H), 3.93-4.19 (m, 6 H), 3.42- 3.77 (m, 5 H), 2.60-2.99 (m, 3 H),1.67-2.41 (m, 7 H), 1.34-1.62 (m, 2 H) M1-(((3S)-1-((3-(2-pyridinyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 708

LCMS-ESI (POS.) m/z: 522.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.15- 8.63 (m, 1 H), 6.83-7.25 (m, 3 H), 4.16-4.51 (m, 3 H), 3.99-4.11(m, 4 H), 3.86-3.98 (m, 2 H), 3.71- 3.83 (m, 1 H), 3.40-3.65 (m, 4 H),2.63-2.90 (m, 3 H), 2.01-2.34 (m, 1 H), 1.64-1.98 (m, 5 H), 1.38- 1.57(m, 2 H), 1.32 (br t, J = 6.94 Hz, 3 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-ethoxy-3-fluorobenzyl)- D-prolinamide 709

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- LCMS-ESI (POS.) m/z:487.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 7.78- 8.19 (m, 1 H),6.98-7.11 (m, 3 H), 4.17-4.45 (m, 3 H), 4.01-4.10 (m, 2 H), 3.88-3.98(m, 2 H), 3.73- 3.85 (m, 1 H), 3.33-3.63 (m, 4 H), 2.62-2.85 (m, 2 H),2.12-2.33 (m, 7 H), 1.67-2.05 (m, 6 H), 1.30- 1.57 (m, 2 H) Apiperidinyl)carbonyl)-N-(2,6-dimethylbenzyl)-D- prolinamide 710

LCMS-ESI (POS.) m/z: 586.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.62- 8.85 (m, 1 H), 8.26-8.47 (m, 1 H), 7.35-7.76 (m, 4 H), 4.21-4.58(m, 4 H), 3.88-4.01 (m, 2 H), 3.51- 3.80 (m, 6 H), 2.61-2.98 (m, 3 H),1.24-2.28 (m, 9 H), 0.67 (br d, J = 5.97 Hz, 4 H) M1-(((3S)-1-((3-((cyclopropylcarbonyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 711

LCMS-ESI (POS.) m/z: 514.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.91- 8.57 (m, 1 H), 6.95-7.27 (m, 4 H), 4.97-5.13 (m, 1 H), 4.23-4.51(m, 1 H), 4.06 (br t, J = 8.24 Hz, 2 H), 3.87-4.00 (m, 2 H), 3.73- 3.85(m, 1 H), 3.41-3.66 (m, 5 H), 2.58-2.91 (m, 5 H), 2.25-2.41 (m, 4 H),1.66-2.23 (m, 6 H), 1.31- 1.57 (m, 2 H) A(2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)pyrrolidine-2- carboxamide 712

1-(((3S)-1-((3-(dimethylcarbamo)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 574.2 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ 7.55- 7.65 (m, 2H), 7.45-7.54 (m,1H), 7.32-7.44 (m, 2H), 4.61 (dd, J = 1.97, 7.98 Hz, 1H), 4.47-4.55 (m,1H), 4.35-4.45 (m, 1H), 4.10- 4.18 (m, 2H), 4.03 (dt, J = 3.84, 8.24 Hz,2H), 3.76- 3.86 (m, 2H), 3.60 (dd, J J = 5.23, 8.76 Hz, 2H), 3.47- 3.56(m, 1H), 2.90-3.01 (m, 4H), 2.86-2.90 (m, 3H), 2.67-2.84 (m, 2H), 2.42-2.52 (m, 1H), 2.11-2.25 (m, 1H), 1.98-2.11 (m, 1H), 1.82-1.95 (m, 2H),1.73- 1.82 (m, 1H), 1.58-1.65 (m, 1H), 1.49-1.58 (m, 1H) J 713

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((4-cyclopropyl-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 472.2 (M +H)⁺ 1H NMR (DMSO-d6) δ: 8.62 (d, J = 7.6 Hz, 1H), 8.53 (d, J = 5.0, 0.8Hz, 1H), 7.65 (dd, J = 9.4, 6.1 Hz, 1H), 7.50 (dd, J = 9.8, 6.3 Hz, 1H),7.46 (s, 1H), 7.31 (dd, J = 5.0, 1.5 Hz, 1H), 4.89 (dd, J = 11.3, 3.4Hz, 1H), 4.51 (t, J = 7.9 Hz, 1H), 3.68-3.56 (m, 1H), 3.22 (td, J = 6.2,2.5 Hz, 1H), 2.27-2.15 (m, 1H), 1.82-1.75 (m, 1H), 1.72 (dd, J = 13.5,3.6 Hz, 1H), 1.22-1.14 (m, 2H), 1.08 (td, J = 5.1, 2.6 Hz, 1H),1.05-0.89 (m, 4H), 0.61-0.50 (m, 1H), 0.50- 0.41 (m, 1H), 0.40-0.30 (m,2H) Q 714

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methyl-5-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 542.0 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.27- 8.70 (m, 1 H), 7.15-7.65 (m, 3H), 4.47-4.57 (m, 1 H), 4.31-4.38 (m, 2 H), 3.97-4.10 (m, 2 H), 3.85-3.97 (m, 2 H), 3.74-3.83 (m, 1 H), 3.30-3.71 (m, 4 H), 2.72-2.91 (m, 2H), 2.62-2.72 (m, 1 H), 2.32- 2.41 (m, 3 H), 1.64-2.27 (m, 6 H),1.37-1.55 (m, 2 H) A 715

N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(3-LCMS-ESI (POS.) m/z: 449.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.65(br d, J = 7.40 Hz, 1 H), 7.90- 8.22 (m, 1 H), 7.52-7.67 (m, 3 H),7.22-7.33 (m, 3 H), 4.50-4.66 (m, 1 H), 4.27-4.35 (m, 1 H), 3.37- 3.60(m, 2 H), 2.29-2.40 (m, 3 H), 2.05-2.21 (m, 1 H), 1.64-1.89 (m, 3 H),1.01-1.26 (m, 1 H), 0.09- 0.65 (m, 4 H) C methylbenzoyl)-D-prolinamide716

LCMS-ESI (POS.) m/z: 528.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.76(br d, J = 7.27 Hz, 1 H), 7.16- 7.79 (m, 8 H), 4.09-4.66 (m, 2 H),3.47-3.69 (m, 1 H), 3.03-3.16 (m, 1 H), 2.23-2.37 (m, 3 H), 2.13- 2.23(m, 1 H), 1.64-1.94 (m, 3 H), 0.76-1.26 (m, 1 H), − 0.13-0.64 (m, 4 H) CN-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(2-methyl-5-sulfamoylbenzoyl)-D-prolinamide 717

(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-methyl-4-pyridinyl)carbonyl)-2-azabicyc1o[3.1.0]hexane-3- carboxamide LCMS- APCI(POS.) m/z: 480.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.52-8.94 (m, 2 H), 7.37-7.61 (m, 3 H), 5.02 (dd, J = 3.9, 11.4 Hz, 1 H),4.45-4.57 (m, 1 H), 3.69-3.90 (m, 1 H), 3.28 (td, J = 2.6, 6.3 Hz, 1 H),2.70 (td, J = 6.0, 12.4 Hz, 1 H), 2.61 (s, 2 H), 1.71-1.99 (m, 3 H),1.28 (qd, J = 4.0, 8.2 Hz, 1 H), 1.16 (td, J = 2.6, 5.3 Hz, 1 H),0.77-0.88 (m, 1 H), 0.70 (tt, J = 4.5, 8.3 Hz, 1 H), 0.53-0.63 (m, 1 H),0.40-0.53 (m, 2 H). Q 718

(1R,3R,5R)-2((4-cyclopropyl-2- pyridinyl)carbonyl)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 504.2 (M +H)⁺ 1H NMR (DMSO-d6) δ: 8.74 (d, J = 8.1 Hz, 1H), 8.52 (d, J = 4.9, 0.8Hz, 1H), 7.70 (d, J = 10.4 Hz, 1H), 7.63-7.56 (m, 1H), 7.48-7.39 (m,1H), 7.31 (dd, J = 5.0, 1.5 Hz, 1H), 5.48 (t, 1H), 4.86 (dd, J = 11.3,3.6 Hz, 1H), 4.65 (t, J = 7.8, 6.4 Hz, 1H), 4.52 (t, 1H), 4.41 (t, J =6.2 Hz, 1H), 4.23 (t, J = 6.1 Hz, 1H), 3.79-3.68 (m, 1H), 3.47-3.37 (m,1H), 3.22 (td, J = 6.1, 2.5 Hz, 1H), 2.28-2.14 (m, 1H), 1.71- 1.62 (m,2H), 1.16-1.06 (m, 1H), 1.03-0.87 (m, 4H), 0.81-0.65 (m, 2H) Q 719

N-(2-chloro-6-fluorobenzyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide LCMS-ESI(POS.) m/z: 512.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.43* (t, J =4.87 Hz, 1 H), 8.07 (t, J = 5.00 Hz, 1 H), 7.31- 7.41 (m, 2 H), 7.23 (t,J = 8.89 Hz, 1 H), 4.43- 4.51 (m, 1 H), 4.36-4.43* (m, 2 H), 4.23-4.30(m, 2 H), 3.99-4.10 (m, 2 H), 3.90-3.99 (m, 2 H), 3.72 3.86 (m, 1 H),3.27-3.63 (m, 4 H), 2.70-2.84 (m, 2 H), 2.55-2.66 (m, 1 H), 2.23-2.35*(m, 1 H), 2.11 -2.21* (m, 1 H), 1.96- 2.04 (m, 1 H), 1.65-1.91 (m, 5 H),1.33-1.54 (m, 2 H) Spectrum appears as 2:1 mixture of rotamers, *denotesresolved minor rotamer peaks A 720

LCMS-ESI (POS.) m/z: 593.4 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.28-8.76 (m, 1H), 7.60-7.74 (m, 2H), 7.37-7.49 (m, 2H), 7.11- 7.34 (m,5H), 4.24-4.51 (m, 4H), 3.43-3.80 (m, 6H), 2.94-3.07 (m, 1H), 2.61- 2.94(m, 4H), 1.67-2.29 (m, 8H), 1.34-1.57 (m, 2H) J(2R)-1-((3S)-1-((2-benzylazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide 721

LCMS-ESI (POS.) m/z: 495.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.46- 8.72 (m, 1 H), 7.30-8.07 (m, 7 H), 6.78-7.22 (m, 1 H), 4.10-4.66(m, 2 H), 3.38-3.64 (m, 2 H), 3.25- 3.26 (m, 1 H), 2.10-2.27 (m, 1 H),1.64-1.90 (m, 3 H), 0.83-1.27 (m, 1 H), 0.26-0.63 (m, 3 H), − 0.11- 0.15(m, 1 H) C N-((R)-cyclopropyl(4-(difluoromethyl)-2-fluorophenyl)methyl)-1-(3- (methylsulfonyl)benzoyl)-D-prolinamide 722

LCMS-ESI (POS.) m/z: 510.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm8.65 (d, J = 1.35 Hz, 1 H), 7.91-7.99 (m, 2 H), 7.80- 7.86 (m, 1 H),7.66-7.75 (m, 3 H), 7.12-7.25 (m, 1 H), 5.14-5.24 (m, 1 H), 4.50-4.64(m, 2 H), 4.18 (td, J = 8.50, 1.76 Hz, 2 H), 4.00-4.07 (m, 2 H), 3.34-3.43 (m, 1 H), 2.89-3.05 (m, 3 H), 1.53 (d, J = 7.05 Hz, 3 H) C3-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1R)-1-methyl-2-oxo-2-(((2-(trifluoromethyl)-4-pyridinyl)methyl)amino)ethyl)benzamide 723

(4S)-N-((R)-(4-chloro-2,5-difluorophenyl)(3-oxetanyl)methyl)-4-hydroxy-1-((2-(trifluoromethyl)-4-pyridinyl)carbonyl)-D- prolinamide LCMS- APCI (POS.)m/z: 520.0 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.92 (d, J = 4.9 Hz,1 H), 8.66 (d, J = 8.3 Hz, 1 H), 7.91 (t, J = 1.1 Hz, 1 H), 7.76-7.88(m, 1 H), 7.57-7.73 (m, 2 H), 7.46 (dd, J = 6.3, 9.8 Hz, 1 H), 7.29 (dd,J = 6.3, 9.7 Hz, 1 H), 5.47 (t, J = 9.1 Hz, 1 H), 5.22 (d, J = 4.9 Hz, 1H), 5.10 (d, J = 3.1 Hz, 1 H), 4.92-5.04 (m, 1 H), 4.66 (dd, J = 6.4,7.7 Hz, 1 H), 4.54 (q, J = 6.8, 7.6 Hz, 2 H), 4.38 (dt, J = 6.6, 24.6Hz, 2 H), 4.19- 4.33 (m, 2 H), 3.88 (t, J = 6.1 Hz, 1 H), 3.71 (dd, J =3.9, 10.8 Hz, 1 H), 3.63 (t, J = 6.1 Hz, 1 H), 3.56 (d, J = 3.4 Hz, 1H), 3.41 (s, 1 H), 3.23 (d, J = 10.9 Hz, 1 H), 3.11 (s, 1 H), 2.04- 2.29(m, 2 H), 1.69-1.93 (m, 2 H). Q 724

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(((2S)-4-(methylsulfonyl)-2-piperazinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 517.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (br d, J = 6.75 Hz, 1 H),7.11 (ddd, J = 12.13, 9.15, 6.23 Hz, 2 H), 4.81 (br d, J = 9.47 Hz, 1H), 4.45 (t, J = 7.85 Hz, 1 H), 4.04 (dd, J = 10.25, 2.85 Hz, 1 H), 3.90(br d, J = 11.42 Hz, 1 H), 3.71 (br d, J = 11.42 Hz, 1 H), 3.47-3.56 (m,1 H), 3.25 (br d, J = 13.23 Hz, 1 H), 3.00-3.11 (m, 1 H), 2.83 (s, 3 H),2.70-2.81 (m, 2 H), 2.57 (br d, J = 13.23 Hz, 1 H), 2.17- 2.35 (m, 2 H),1.56-1.80 (m, 1 H), 1.09-1.20 (m, 1 H), 0.92-0.98 (m, 1 H), 0.88-0.92(m, 1 H), 0.56- 0.65 (m, 1 H), 0.48-0.56 (m, 1 H), 0.36 (tq, J = 13.35,4.60 Hz, 2 H) M 725

LCMS- APCI (POS.) m/z: 523.1 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 9.02- 9.13 (m, 2 H), 7.96-8.17 (m, 2 H), 7.69-7.96 (m, 2 H),4.40-4.82 (m, 3 H), 4.03-4.16 (m, 2 H), 3.88- 3.97 (m, 2 H), 3.46-3.85(m, 3 H), 2.30-2.47 (m, 1 H), 1.88-2.25 (m, 3 H). A 1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((5-(trifluoromethyl)-2-pyrimidinyl)methyl)-D- prolinamide 726

LCMS-ESI (POS.) m/z: 517.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.48- 8.73 (m, 1 H), 7.21-8.02 (m, 10 H), 4.49-4.63 (m, 1 H), 4.19-4.39(m, 1 H), 3.45-3.64 (m, 2 H), 2.12- 2.28 (m, 1 H), 1.63-1.94 (m, 3 H),0.83-1.28 (m, 1 H), − 0.17-0.76 (m, 4 H) CN-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(3-(3-thiophenyl)benzoyl)-D-prolinamide 727

(1R,3R,5R)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-(4-methyl-3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 555.2 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (d, J = 8.1 Hz, 1 H), 8.28 (d,J = 1.8 Hz, 1 H), 7.92 (dd, J = 1.9, 7.8 Hz, 1 H), 7.70 (d, J = 10.3 Hz,1 H), 7.60 (p, J = 6.9, 7.9 Hz, 3 H), 5.48 (t, J = 8.9 Hz, 1 H), 4.91(dd, J = 3.7, 11.3 Hz, 1 H), 4.65 (t, J = 7.0 Hz, 1 H), 4.51 (t, J = 7.1Hz, 1 H), 4.41 (t, J = 6.2 Hz, 1 H), 4.22 (t, J = 6.2 Hz, 1 H),3.38-3.47 (m, 1 H), 3.27 (s, 4 H), 2.70 (s, 3 H), 2.56 (dd, J = 6.2,12.5 Hz, 1 H), 1.60- 1.77 (m, 2 H), 1.14 (d, J = 2.7 Hz, 1 H), 0.78 (dt,J = 5.2, 10.2 Hz, 1 H). Q 728

(1R,3R,5R)-N-((R)-(2,4-difluorophenyl)(3-oxetanyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyc1o[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 491.1 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.39 (t, J = 1.7 Hz, 1 H), 8.09-8.20 (m, 2 H), 7.78 (t, J = 7.8 Hz, 1 H), 7.37 (td, J = 6.3, 8.7 Hz, 1H), 6.96 7.09 (m, 2 H), 5.59 (d, J = 10.2 Hz, 1 H), 4.99 (dd, J = 4.1,11.4 Hz, 1 H), 4.79- 4.86 (m, 1 H), 4.56-4.71 (m, 2 H), 4.36 (t, J = 6.2Hz, 1 H), 3.46-3.63 (m, 1 H), 3.19 (s, 3 H), 2.55- 2.73 (m, 1 H), 1.90(dd, J = 4.3, 13.5 Hz, 1 H), 1.75- 1.84 (m, 1 H), 1.27 (td, J = 2.7, 5.3Hz, 1 H), 0.90 (dtd, J = 1.1, 5.7, 9.0 Hz, 1 H). A 729

LCMS-ESI (POS.) m/z: 492.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.06- 8.59 (m, 1 H), 7.26-7.41 (m, 2 H), 7.06-7.19 (m, 2 H), 4.80-5.01(m, 1 H), 4.25-4.49 (m, 1 H), 4.01- 4.14 (m, 2 H), 3.88-3.99 (m, 2 H),3.72-3.83 (m, 1 H), 3.48-3.70 (m, 4 H), 2.59-2.91 (m, 3 H), 1.62- 2.30(m, 6 H), 1.24-1.59 (m, 5 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4- fluorophenyl)ethyl)-D-prolinamide,1-(((3S)-1-((3- cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(4- fluorophenyl)ethyl)-D-prolinamide730

1-(((3S)-1-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 533.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.53-7.65 (m, 2 H), 7.30- 7.45(m, 3 H), 4.59 (dd, J = 7.91, 1.69 Hz, 1 H), 4.51 (dd, J = 15.44, 6.36Hz, 1 H), 4.34-4.48 (m, 1 H), 3.67-3.92 (m, 6 H), 3.53- 3.65 (m, 2 H),2.89-3.05 (m, 1 H), 2.67-2.82 (m, 3 H), 2.43 (ddd, J = 9.41, 6.55, 3.24Hz, 1 H), 2.13-2.36 (m, 2 H), 1.99-2.10 (m, 1 H), 1.74-1.96 (m, 4 H),1.46-1.71 (m, 4 H) M 731

(1S,3R,5S)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 544.2 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.83-8.95 (m, 1 H), 8.38- 8.46(m, 1 H), 7.75-7.89 (m, 1 H), 7.39 (br d, J = 6.53 Hz, 1 H), 7.33 (dd, J= 9.43, 5.60 Hz, 1 H), 7.20 (dd, J = 10.00, 5.55 Hz, 1 H), 4.70-4.87 (m,1 H), 4.42- 4.53 (m, 1 H), 3.29 (s, 3 H), 3.16-3.23 (m, 1 H), 2.76 (ddd,J = 13.48, 7.31, 2.95 Hz, 1 H), 1.95-2.17 (m, 2 H), 1.04-1.33 (m, 2 H),0.66-0.80 (m, 2 H), 0.57-0.65 (m, 1 H), 0.34- 0.52 (m, 2 H) C 732

(2S)-N-((R)-(4-chloro-2,5- difluorophenyl)(cyclopropyl)methyl)-1-(3-(methylsulfonyl)benzoyl)-2-azetidinecarboxamide LCMS-ESI (POS.) m/z:483.0 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.26 (br s, 1 H),8.05-8.19 (m, 2 H), 7.98 (br d, J = 7.53 Hz, 1 H), 7.74 (br t, J = 7.66Hz, 1 H), 7.10-7.23 (m, 2 H), 5.11 (br dd, J = 8.89, 6.94 Hz, 1 H),4.33-4.62 (m, 2 H), 4.17-4.25 (m, 1 H), 3.12 (s, 3 H), 2.78- 2.91 (m, 1H), 2.44-2.59 (m, 1 H), 1.12-1.32 (m, 1 H), 0.59-0.68 (m, 1 H),0.50-0.59 (m, 1 H), 0.33- 0.50 (m, 2 H) C 733

N-((1R)-1-(4-chlorophenyl)-2-hydroxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- LCMS-ESI (POS.) m/z: 524.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.06- 8.53 (m, 1 H), 7.27-7.44(m, 1 H), 7.20-7.55 (m, 3 H), 5.81-5.96 (m, 1 H), 4.73-4.90 (m, 1 H),4.32- 4.52 (m, 1 H), 3.98-4.10 (m, 2 H), 3.86-3.98 (m, 2 H), 3.69-3.84(m, 1 H), 3.30-3.68 (m, 6 H), 2.67- 2.91 (m, 2 H), 2.54-2.66 (m, 1 H),2.01-2.30 (m, 1 H), 1.67-1.99 (m, 5 H), 1.21-1.53 (m, 2 H) Apiperidinyl)carbonyl)-D-prolinamide 734

LCMS-ESI (POS.) m/z: 575.3 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.18- 8.93 (m, 1 H), 7.58-7.77 (m, 2 H), 7.45 (br d, J = 7.79 Hz, 2 H),4.42-4.57 (m, 2 H), 4.23-4.42 (m, 3 H), 3.77-3.98 (m, 2 H), 3.52- 3.71(m, 6 H), 2.61-2.83 (m, 3 H), 1.31-2.28 (m, 10 H), 1.08-1.14 (m, 9 H) M1-(((3S)-1-((3-tert-butoxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 735

LCMS-ESI (POS.) m/z: 573.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.28-8.75 (m, 1H), 7.61-7.74 (m, 2H), 7.34-7.53 (m, 2H), 4.25- 4.53 (m,3H), 3.75-3.89 (m, 2H), 3.40-3.70 (m, 6H), 2.59-2.84 (m, 3H), 2.04- 2.34(m, 1H), 1.67-2.00 (m, 5H), 1.14-1.58 (m, 11H), 0.77-0.92 (m, 3H) J1-(((3S)-1-((3-pent-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 736

(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((2-methyl-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS-APCI (POS.) m/z: 446.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm8.52- 8.82 (m, 1 H), 7.52-7.66 (m, 1 H), 7.35 (dd, J = 6.1, 9.5 Hz, 2H), 5.00 (dd, J = 3.8, 11.4 Hz, 1 H), 4.45- 4.56 (m, 1 H), 3.69-3.80 (m,1 H), 3.13-3.30 (m, 1 H), 2.57-2.76 (m, 3 H), 1.71-1.93 (m, 2 H), 1.12-1.40 (m, 2 H), 0.37-0.89 (m, 4 H). Q 737

N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(1H-pyrazol-4-yl)benzoyl)-D-prolinamide LCMS-ESI (POS.) m/z: 501.2 (M + H)⁺ 1H NMR(600 MHz, DMSO-d6) δ ppm 12.83- 13.24 (m, 1 H), 8.53-8.79 (m, 1 H),8.12-8.37 (m, 1 H), 7.89-8.07 (m, 1 H), 7.11-7.75 (m, 6 H), 4.50- 4.65(m, 1 H), 4.19-4.40 (m, 1 H), 3.45-3.64 (m, 2 H), 3.39-3.41 (m, 1 H),2.11-2.29 (m, 1 H), 1.63- 1.92 (m, 3 H), 0.90-1.30 (m, 1 H), −0.13-0.64(m, 4 H) C 738

(1R,3R,5R)-N-((R)-(4-chloro-2-fluorophenyl)(3-oxetanyl)methyl)-2-((2-(2-methyl-2-propanyl)-4-pyridinyl)carbonyl)-2-azabicyc1o[3.1.0]hexane-3- carboxamide LCMS- APCI(POS.) m/z: 486.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.64 (dd,J = 0.9, 5.0 Hz, 1 H), 7.82 (dd, J = 0.9, 1.5 Hz, 1 H), 7.51 (dd, J =1.5, 5.0 Hz, 1 H), 7.33 (t, J = 8.2 Hz, 1 H), 7.22-7.27 (m, 2 H), 5.58(d, J = 10.2 Hz, 1 H), 4.95 (dd, J = 4.1, 11.4 Hz, 1 H), 4.84 (dd, J =6.5, 7.6 Hz, 1 H), 4.60-4.69 (m, 2 H), 4.37 (t, J = 0.8, 12.5 Hz, 1 H),3.48-3.58 (m, 1 H), 3.37 (s, 1 H), 3.26 (td, J = 2.6, 6.2 Hz, 1 H),2.60-2.69 (m, 1 H), 1.90 (dd, J = 4.1, 13.5 Hz, 1 H), 1.75-1.82 (m, 1H), 1.42 (s, 10 H), 1.25 (dt, J = 2.7, 5.3 Hz, 1 H), 0.81- 0.89 (m, 1H). A 739

LCMS-ESI (POS.) m/z: 573.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.24-8.79 (m, 1H), 7.58-7.76 (m, 2H), 7.36-7.52 (m, 2H), 4.19- 4.52 (m,3H), 3.41-3.92 (m, 12H), 2.59-2.86 (m, 3H), 2.37-2.46 (m, 1H), 2.05-2.37 (m, 2H), 1.63-2.05 (m, 6H), 1.32-1.56 (m, 3H) J(2R)-1-((3S)-1-((3-(tetrahydrofuran-3-yl)azetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide 740

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-2,2-dimethyl-1-(4- LCMS-ESI (POS.) m/z:584.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.14- 8.60 (m, 1 H),7.61-7.76 (m, 2 H), 7.40-7.55 (m, 2 H), 4.68-4.78 (m, 1 H), 4.46-4.64(m, 1 H), 4.02- 4.13 (m, 2 H), 3.90-3.99 (m, 2 H), 3.74-3.84 (m, 1 H),3.31-3.63 (m, 4 H), 2.79-2.92 (m, 1 H), 2.58- 2.74 (m, 1 H), 2.15-2.34(m, 1 H), 1.58-2.06 (m, 6 H), 1.32-1.54 (m, 2 H), 0.76-0.95 (m, 9 H) A(trifluoromethyl)phenyl)propyl)-D-prolinamide 741

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(5-methyl-2-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 542.0 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.24- 8.70 (m, 1 H), 7.32-7.58 (m, 3H), 5.07-5.09 (m, 1 H), 4.19-4.56 (m, 3 H), 4.00-4.15 (m, 2 H), 3.85-4.00 (m, 2 H), 3.74-3.86 (m, 1 H), 3.29-3.71 (m, 4 H), 2.70-2.87 (m, 2H), 2.60-2.70 (m, 1 H), 2.28- 2.37 (m, 3 H), 1.62-2.16 (m, 6 H),1.28-1.55 (m, 2 H) A 742

LCMS-ESI (POS.) m/z: 481.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.20- 8.44 (m, 1 H), 7.21-8.09 (m, 7 H), 5.01-5.44 (m, 1 H), 4.23-4.51(m, 1 H), 3.43-3.70 (m, 2 H), 3.22- 3.28 (m, 3 H), 2.72-3.07 (m, 2 H),2.10-2.46 (m, 2 H), 1.32-2.01 (m, 4 H) A1-(3-(methylsulfonyl)benzoyl)-N-((1R)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-)-D- prolinamide 743

LCMS-ESI (POS.) m/z: 627.4 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.16-8.81 (m, 1H), 7.62-7.75 (m, 2H), 7.37-7.53 (m, 2H), 6.42- 6.58 (m,1H), 4.22-4.51 (m, 3H), 3.73-3.88 (m, 4H), 3.42-3.69 (m, 4H), 2.69- 2.86(m, 2H), 2.56-2.69 (m, 3H), 2.29-2.42 (m, 2H), 2.03-2.27 (m, 1H), 1.65-2.03 (m, 5H), 1.32-1.53 (m, 2H) J1-(((3S)-1-((6-hydroxy-6-(trifluoromethyl)-2-azaspiro[3.3]hept-2-yl)sulfonyl)-3- piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 744

1-(((3S)-1-(dimethylsulfamo)-3- piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 491.2 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.72* (t, J = 6.00 Hz, 1 H), 8.36(t, J = 6.03 Hz, 1 H), 7.64- 7.71 (m, 2 H), 7.45 (d, J = 7.98 Hz, 2 H),4.28- 4.49 (m, 3 H), 3.33-3.68 (m, 4 H), 2.76-2.89 (m, 2 H), 2.74 (s, 6H), 2.72* (s, 6 H), 2.64-2.68 (m, 1 H), 2.28-2.36* (m, 1 H), 2.17 -2.26*(m, 1 H), 2.06- 2.14 (m, 1 H), 1.67-1.99 (m, 5 H), 1.37-1.55 (m, 2 H).Spectrum appears as 2:1 mixture of rotamers, *denotes resolved minorrotamer peaks. M 745

LCMS-ESI (POS.) m/z: 501.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.32- 8.85 (m, 1 H), 7.12-8.03 (m, 9 H), 6.66-6.83 (m, 1 H), 4.54-4.63(m, 1 H), 4.24-4.34 (m, 1 H), 3.48- 3.61 (m, 2 H), 2.11-2.26 (m, 1 H),1.70-1.92 (m, 3 H), 0.92-1.28 (m, 1 H), − 0.11-0.69 (m, 4 H) CN-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(1H-pyrazol-3-yl)benzoyl)-D-prolinamide 746

LCMS-ESI (POS.) m/z: 528.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.33- 8.74 (m, 1 H), 7.60-7.74 (m, 2 H), 7.40-7.55 (m, 2 H), 4.31-4.56(m, 3 H), 3.99-4.10 (m, 2 H), 3.87- 3.98 (m, 2 H), 3.73-3.83 (m, 1 H),3.35-3.70 (m, 4 H), 2.65-2.88 (m, 2 H), 1.69-2.35 (m, 7 H), 1.35- 1.57(m, 2 H) A 1-(((35)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2- (trifluoromethyl)benzyl)-D-prolinamide 747

(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-methoxyphenyl)methyl)-2-(3- (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 505.2 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.20- 8.53 (m, 1 H) 7.88-8.20 (m, 3H) 7.64-7.82 (m, 1 H) 7.02-7.32 (m, 2 H) 4.59-4.96 (m, 1 H) 4.08- 4.58(m, 1 H) 3.79-3.88 (m, 3 H) 3.21-3.28 (m, 4 H) 2.52-2.59 (m, 1 H)1.53-1.74 (m, 2 H) 0.79- 1.18 (m, 2 H) 0.67-0.77 (m, 1 H)-0.26-0.54 (m,4 H) C 748

(1R,3R,5R)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((2-(2-propanyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 506.2 (M +H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 8.79 (d, J = 8.0 Hz, 1 H), 8.60(dd, J = 0.9, 5.1 Hz, 1 H), 7.66 (t, J = 1.2 Hz, 1 H), 7.46-7.60 (m, 4H), 5.63- 5.70 (m, 1 H), 4.97 (dd, J = 4.0, 11.4 Hz, 1 H), 4.83- 4.87(m, 1 H), 4.59-4.70 (m, 2 H), 4.40 (t, 1 H), 3.50- 3.61 (m, 1 H), 3.27(td, J = 2.6, 6.2 Hz, 1 H), 3.16 (dt, J = 6.9, 13.9 Hz, 1 H), 2.66(dddd, J = 1.1, 6.4, 11.6, 13.3 Hz, 1 H), 1.90 (dd, J = 4.1, 13.5 Hz, 1H), 1.74-1.83 (m, 1 H), 1.35 (dd, J = 2.1, 7.0 Hz, 7 H), 1.23 (td, J =2.6, 5.3 Hz, 1 H), 0.80-0.88 (m, 1 H). Q 749

LCMS-ESI (POS.) m/z: 522.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.49- 8.91 (m, 1 H), 7.50-8.04 (m, 8 H), 4.84-5.27 (m, 1 H), 3.99-4.48(m, 2 H), 3.59-3.68 (m, 1 H), 3.39- 3.54 (m, 3 H), 2.69-3.15 (m, 4 H),2.69-3.19 (m, 1 H), 1.68-2.06 (m, 4 H), 1.31-1.46 (m, 3 H) D1-(3-(methyl(2-propyn-1-)sulfamoyl)benzoyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D- prolinamide 750

1-(((3S)-1-(((6R)-6-hydroxy-2-azaspiro[3.4]oct-2-yl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide, 1-(((3S)-1-(((6S)-6-hydroxy-2-azaspiro[3.4]oct-2-yl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 629.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (d, J = 8.04 Hz, 2 H),7.43 (br s, 1 H), 7.28-7.39 (m, 2 H), 4.59 (br d, J = 6.75 Hz, 1 H),4.47-4.56 (m, 1 H), 4.30-4.47 (m, 2 H), 3.89 (dd, J = 7.53, 3.63 Hz, 1H), 3.70-3.83 (m, 5 H), 3.53-3.66 (m, 2 H), 2.81- 3.02 (m, 3 H),2.60-2.81 (m, 3 H), 2.30-2.46 (m, 1 H), 1.98-2.21 (m, 4 H), 1.75-1.96(m, 6 H), 1.58- 1.71 (m, 2 H), 1.45-1.58 (m, 1 H), 1.42 (br s, 1 H),1.02 (br s, 1 H), 0.37 (br s, 1H) M 751

LCMS-ESI (POS.) m/z: 525.3 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm7.18- 8.62 (m, 8 H), 3.54-4.69 (m, 3 H), 3.04 (br s, 2 H), 3.29 (br s, 1H), 1.76-2.34 (m, 4 H), 0.86-1.62 (m, 2 H),-0.09-0.73 (m, 4 H) C(1R,5R)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3- (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-1-carboxamide 752

LCMS-ESI (POS.) m/z: 508.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.62(br d, J = 7.53 Hz, 1 H), 8.21- 8.43 (m, 1 H), 7.29-8.20 (m, 5 H),4.61-5.02 (m, 1 H), 3.96-4.57 (m, 1 H), 3.04-3.88 (m, 5 H), 2.52- 2.79(m, 2 H), 1.53-1.86 (m, 2 H), 1.02-1.35 (m, 2 H),-0.29-0.97 (m, 6 H) Q(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(3-(S-methylsulfonimidoyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide753

(1R,3R,5R)-N-((1R)-5-chloro-2,3-dihydro-1H-inden-1-)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 459.2 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J = 8.1 Hz, 1 H), 8.22 (t,J = 1.8 Hz, 1 H), 8.06 (ddt, J = 1.4, 7.8, 10.6 Hz, 2 H), 7.75-7.85 (m,1 H), 7.23- 7.38 (m, 2 H), 7.16 (d, J = 8.1 Hz, 1 H), 5.23 (q, J = 8.0Hz, 1 H), 4.90 (dd, J = 3.7, 11.4 Hz, 1 H), 3.28 (s, 4 H), 2.94 (ddd, J= 3.3, 8.9, 16.4 Hz, 1 H), 2.77- 2.88 (m, 1 H), 2.57-2.68 (m, 1 H), 2.39(dtd, J = 3.3, 7.9, 11.5 Hz, 1 H), 1.81- 1.99 (m, 2 H), 1.74 (dq, J =6.0, 8.7 Hz, 1 H), 1.34 (td, J = 2.6, 5.1 Hz, 1 H), 0.77- 0.95 (m, 1 H).A 754

LCMS-ESI (POS.) m/z: 600.4 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.25- 8.76 (m, 2 H), 7.59-7.77 (m, 2 H), 7.45 (br d, J = 7.79 Hz, 2 H),4.25-4.57 (m, 4 H), 3.85-4.01 (m, 2 H), 3.51-3.75 (m, 6 H), 2.92- 3.06(m, 1 H), 2.57-2.89 (m, 3 H), 1.68-2.18 (m, 12 H), 1.33-1.58 (m, 2 H) M1-(((3S)-1-((3-((cyclobutylcarbonyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 755

(1R,3R,5R)-2-(2-aminobenzoyl)-N-((R)- cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS- APCI (POS.) m/z: 462.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm10.91 (s, 1 H), 8.73 (d, J = 7.5 Hz, 1 H), 7.69 (q, J = 10.0, 10.8 Hz, 3H), 7.54 (d, J = 7.5 Hz, 1 H), 7.36 (s, 1 H), 7.09 (t, J = 7.5 Hz, 1 H),6.50 (s, 1 H), 5.09 (d, J = 12.3 Hz, 1 H), 4.63 (t, J = 7.8 Hz, 1 H),1.72-1.81 (m, 1 H), 1.54-1.71 (m, 1 H), 1.12-1.26 (m, 1 H), 0.66-0.77(m, 1 H), 0.52- 0.63 (m, 1 H), 0.39-0.52 (m, 1 H), 0.37 (s, 2 H). Q 756

(3R)-N-((R)-cyclopropyl(4-(trifluoromethyl)phenyl)methyl)-3-fluoro-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide LCMS-ESI (POS.) m/z: 513.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.13 (s, 1 H), 8.04-8.11 (m, 1H), 7.84 (d, J = 7.66 Hz, 1 H), 7.67-7.75 (m, 1 H), 7.57-7.66 (m, 3 H),7.47-7.53 (m, 2 H), 5.34- 5.57 (m, 1 H), 4.83-5.10 (m, 1 H), 4.41 (t, J= 7.85 Hz, 1 H), 3.57-3.78 (m, 2 H), 3.04-3.17 (m, 3 H), 2.22-2.60 (m, 2H), 1.11- 1.31 (m, 1 H), 0.54-0.74 (m, 2 H), 0.30-0.52 (m, 2 H) C 757

LCMS-ESI (POS.) m/z: 513.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.52(d, J = 8.56 Hz, 1 H) 7.18-8.19 (m, 6 H) 4.46-4.97 (m, 3 H) 3.67-3.89(m, 1 H) 3.23-3.28 (m, 4 H) 2.52- 2.58 (m, 1 H) 1.50-1.75 (m, 2 H)0.91-1.16 (m, 4 H) 0.68-0.83 (m, 1 H) A(1R,3R,5R)-N-(1-(4-chloro-2,5-difluorophenyl)-2-hydroxypropyl)-2-(3-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 758

N-benzyl-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D- prolinamide LCMS-ESI(POS.) m/z: 460.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.18-7.38 (m, 5 H), 4.62 (br d, J = 5.97 Hz, 1 H), 4.40- 4.50 (m, 2 H),4.10-4.17 (m, 4 H), 3.78 (br d, J = 12.07 Hz, 2 H), 3.57- 3.66 (m, 2 H),3.42-3.49 (m, 1 H), 2.97-3.02 (m, 1 H), 2.69-2.82 (m, 2 H), 2.44-2.49(m, 1 H), 2.18- 2.26 (m, 1 H), 1.49-2.14 (m, 7 H) A 759

1-((3-((3-cyano-1- azetidinyl)sulfonyl)phenyl)carbonyl)-N-(cis-3-(trifluoromethyl)cyclobut)-D-prolinamide, 1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-(trans-3-(trifluoromethyl)cyclobut)-D- prolinamide LCMS- APCI (NEG.)m/z: 483.1 (M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm 8.11 (d, J = 1.9Hz, 1 H), 7.92- 8.02 (m, 2 H), 7.76-7.82 (m, 1 H), 4.39-4.54 (m, 2 H),4.07-4.13 (m, 2 H), 3.90-3.95 (m, 2 H), 3.66 (dt, J = 7.0, 10.1 Hz, 1H), 3.53 (tdd, J = 3.7, 6.5, 8.8 Hz, 2 H), 3.00 (dtt, J = 5.3, 10.4,15.8 Hz, 1 H), 2.53 (tt, J = 4.3, 9.0 Hz, 2 H), 2.26-2.46 (m, 4 H),1.86- 2.07 (m, 4 H). A 760

LCMS-ESI (POS.) m/z: 589.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.21- 8.82 (m, 1 H), 7.60-7.79 (m, 2 H), 7.46 (br d, J = 7.53 Hz, 2 H),4.08-4.56 (m, 7 H), 3.40-3.75 (m, 4 H), 2.55-2.98 (m, 3 H), 1.66- 2.43(m, 6 H), 1.32-1.60 (m, 2 H) M1-(((3S)-1-((3-fluoro-3-(trifluoromethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 761

LCMS-ESI (POS.) m/z: 514.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.39- 8.98 (m, 2 H), 7.26-8.14 (m, 5 H), 4.13-4.67 (m, 2 H), 3.37-3.60(m, 2 H), 3.17-3.35 (m, 3 H), 2.17- 2.37 (m, 1 H), 1.64-2.03 (m, 3 H),0.87-1.29 (m, 1 H),-0.13-0.68 (m, 3 H), − 0.19-0.70 (m, 1 H) C(2R)-N-(cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(2-(methylsulfonyl)isonicotinoyl)pyrrolidine-2- carboxamide 762

(1S,3R,5S)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-(3- (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 525.0 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.31-8.42 (m, 1 H), 8.08 (br d,J = 7.78 Hz, 1 H), 8.03 (br d, J = 7.78 Hz, 1 H), 7.71 (t, J = 7.72 Hz,1 H), 7.57 (br d, J = 7.14 Hz, 1 H), 7.45- 7.52 (m, 1 H), 7.39-7.45 (m,1 H), 7.35 (d, J = 10.38 Hz, 1 H), 4.76 (dd, J = 8.24, 2.66 Hz, 1 H),4.59 (br t, J = 7.91 Hz, 1 H), 3.22 (br t, J = 4.87 Hz, 1 H), 3.11 (s, 3H), 2.77 (ddd, J = 13.27, 7.30, 2.40 Hz, 1 H), 2.06 (br dd, J = 12.91,9.28 Hz, 1 H), 1.95-2.03 (m, 1 H), 1.29-1.36 (m, 1 H), 1.08 (dt, J =8.50, 5.48 Hz, 1 H), 0.71-0.80 (m, 1 H), 0.63- 0.71 (m, 1 H), 0.53-0.63(m, 1 H), 0.48 (dq, J = 9.59, 4.76 Hz, 1 H), 0.35-0.45 (m, 1 H) C 763

LCMS-ESI (POS.) m/z: 510.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.21- 8.85 (m, 1 H), 7.05-7.42 (m, 3 H), 5.00-5.22 (m, 1 H), 4.26-4.52(m, 1 H), 3.70-4.12 (m, 6 H), 3.42- 3.65 (m, 4 H), 2.59-2.92 (m, 3 H),2.12-2.38 (m, 1 H), 1.38-2.12 (m, 9 H) A(2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(1-(2,3-difluorophenyl)ethyl)pyrrolidine-2-carboxamide 764

LCMS-ESI (POS.) m/z: 528.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm8.05 (s, 1 H), 7.95 (br d, J = 7.98 Hz, 1 H), 7.72 (d, J = 7.72 Hz, 1H), 7.52- 7.63 (m, 3 H), 7.28-7.44 (m, 3 H), 5.50-5.70 (m, 1 H), 4.77(dd, J = 7.28, 5.36 Hz, 1 H), 4.53 (d, J = 5.96 Hz, 2 H), 3.80 (d, J =5.55 Hz, 2 H), 3.57-3.68 (m, 4 H), 3.41-3.53 (m, 1 H), 2.38-2.51 (m, 1H), 2.01- 2.25 (m, 3 H), 1.81-2.01 (m, 1 H), 1.70 (br s, 2 H) B methylN-((3-(((2R)-2-((4- (trifluoromethyl)benzyl)carbamo)-1-pyrrolidinyl)carbonyl)phenyl)sulfonyl)glycinate 765

LCMS-ESI (POS.) m/z: 488.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.05- 8.43 (m, 1 H), 6.91-7.09 (m, 3 H), 4.32-4.51 (m, 1 H), 4.13-4.32(m, 2 H), 4.00-4.12 (m, 2 H), 3.86- 3.99 (m, 2 H), 3.73-3.81 (m, 1 H),3.43-3.71 (m, 5 H), 2.62-2.89 (m, 3 H), 2.14-2.33 (m, 6 H), 1.69- 2.11(m, 5 H), 1.36-1.57 (m, 2 H) A1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,5-dimethylbenzyl)-D- prolinamide 766

(2R)-1-((3S)-1-((tetrahydrofuran-3-yl)sulfonyl)piperidine-3-carbonyl)-N-(4- LCMS- APCI (POS.) m/z: 518.2(M + H)⁺ 1H NMR (Methanol-d4) δ: 7.78-7.59 (m, 1H), 7.58- 7.43 (m, 1H),4.68-4.38 (m, 4H), 3.83 (d, J = 11.9 Hz, 2H), 3.77-3.70 (m, 6H),3.01-2.73 (m, 2H), 2.64 (ddd, J = 20.9, 14.6, 8.6 Hz, 4H), 2.26 (dt, J =14.8, 7.8 Hz, 2H), 2.18- 1.89 (m, 2H), 1.90-1.72 (m, 2H), 1.72-1.46 (m,4H) R (trifluoromethyl)benzyl)pyrrolidine-2-carboxamide 767

N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-3,3-difluoro-1-(5-(methylsulfonyl)nicotinoyl)azetidine-2- LCMS-ESI (POS.) m/z: 554.0 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.03-9.37 (m, 2 H), 8.34- 8.67(m, 1 H), 7.30-7.41 (m, 1 H), 7.06-7.27 (m, 1 H), 6.65-7.04 (m, 1 H),5.13-5.41 (m, 1 H), 4.65- 4.89 (m, 1 H), 4.49-4.64 (m, 1 H), 4.25-4.48(m, 1 H), 3.08-3.25 (m, 3 H), 1.11-1.47 (m, 1 H), 0.27- 0.86 (m, 4 H) Ccarboxamide 768

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide LCMS-ESI (POS.) m/z: 596.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 9.19- 9.50 (m, 1 H), 7.74-7.89(m, 4 H), 5.85-6.05 (m, 1 H), 4.46 (dd, J = 8.43, 4.15 Hz, 1 H),3.97-4.08 (m, 2 H), 3.84-3.95 (m, 2 H), 3.71-3.80 (m, 1 H), 3.50- 3.61(m, 3 H), 2.69-2.81 (m, 2 H), 2.57-2.66 (m, 1 H), 2.12-2.23 (m, 1 H),1.86-1.99 (m, 2 H), 1.73- 1.84 (m, 2 H), 1.62-1.70 (m, 1 H), 1.48 (qt, J= 12.82, 3.60 Hz, 1 H), 1.24-1.37 (m, 1 H) A 769

LCMS-ESI (POS.) m/z: 517.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.27- 8.82 (m, 1 H), 7.58-7.83 (m, 2 H), 7.45 (br d, J = 7.79 Hz, 2 H),4.12-4.50 (m, 4 H), 3.43-3.84 (m, 7 H), 2.59-2.87 (m, 3 H), 2.03- 2.40(m, 3 H), 1.65-2.01 (m, 7 H), 1.33-1.61 (m, 2 H), 1.22-1.31 (m, 3 H) M(2R)-1-((3S)-1-((2-methylazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide 770

N-(5-chloro-2-methoxybenzyl)-1-(((3S)-1-((3- LCMS-ESI (POS.) m/z: 524.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.06- 8.53 (m, 1 H), 7.07-7.33(m, 2 H), 6.92-7.05 (m, 1 H), 4.11-4.54 (m, 3 H), 3.90-4.10 (m, 4 H),3.74- 3.85 (m, 4 H), 3.45-3.72 (m, 4 H), 2.62-2.89 (m, 3 H), 2.06-2.35(m, 1 H), 1.66-2.35 (m, 5 H), 1.36- 1.58 (m, 2 H) Acyano-1-azetidinyl)sulfonyl)-3- piperidinyl)carbonyl)-D-prolinamide 771

LCMS-ESI (POS.) m/z: 647.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.27-8.74 (m, 1H), 7.54-7.79 (m, 6H), 7.36-7.51 (m, 2H), 4.26- 4.45 (m,3H), 4.10-4.26 (m, 2H), 3.83-4.05 (m, 3H), 3.46-3.73 (m, 5H), 2.62- 2.90(m, 3H), 2.05-2.42 (m, 1H), 1.37-2.05 (m, 6H) JN-(4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-(3-(trifluoromethyl)phenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide 772

LCMS-ESI (POS.) m/z: 467.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.15- 8.45 (m, 1 H), 6.97-8.10 (m, 7 H), 4.32-4.81 (m, 2 H), 3.42-3.61(m, 2 H), 3.20-3.32 (m, 3 H), 2.12- 2.31 (m, 1 H), 1.28-1.97 (m, 5 H),0.36-1.01 (m, 3 H) C N-((lR)-1-(4-chloro-3-fluorophenyl)propyl)-1-(3-(methylsulfonyl)benzoyl)-D-prolinamide 773

LCMS-ESI (POS.) m/z: 553.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.30- 8.83 (m, 1 H), 7.58-7.75 (m, 2 H), 7.45 (br d, J = 7.79 Hz, 2 H),4.24-4.55 (m, 3 H), 3.56-3.70 (m, 5 H), 3.34-3.49 (m, 3 H), 2.78- 2.93(m, 2 H), 2.58-2.71 (m, 1 H), 2.37-2.48 (m, 2 H), 1.35-2.20 (m, 8 H) M1-(((3S)-1-((3,3-difluoro-1-pyrrolidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 774

LCMS-ESI (POS.) m/z: 559.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.30-8.79 (m, 1H), 7.90-8.15 (m, 1H), 7.60-7.76 (m, 2H), 7.36- 7.54 (m,2H), 4.21-4.52 (m, 5H), 3.38-3.72 (m, 5H), 2.53-2.75 (m, 4H), 1.64- 2.37(m, 7H), 1.27-1.49 (m, 2H) J 1-(((3S)-1-(((5-methyl-1,3,4-oxadiazol-2-yl)methyl)sulfamo)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 775

LCMS- APCI (POS.) m/z: 560.2 (M + H)⁺ 1H NMR (Methanol-d4) δ: 7.78-7.59(m, 1H), 7.58- 7.43 (m, 1H), 4.68-4.38 (m, 4H), 3.83 (d, J = 11.9 Hz,2H), 3.77-3.70 (m, 6H), 3.01-2.73 (m, 2H), 2.64 (ddd, J = 20.9, 14.6,8.6 Hz, 4H), 2.26 (dt, J = 14.8, 7.8 Hz, 2H), 2.18- 1.89 (m, 2H),1.90-1.72 (m, 2H), 1.72-1.46 (m, 4H) R methyltrans-3-(((3S)-3-(((2R)-2-((4- (trifluoromethyl)benzyl)carbamo)-1-pyrrolidinyl)carbonyl)-1-piperidinyl)sulfonyl)cyclobutanecarboxylate 776

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- LCMS-ESI (POS.) m/z:576.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.88- 9.45 (m, 1 H),7.09-7.50 (m, 3 H), 5.59-5.85 (m, 1 H), 4.35-4.61 (m, 1 H), 4.00-4.14(m, 2 H), 3.89- 3.97 (m, 2 H), 3.74-3.89 (m, 4 H), 3.41-3.67 (m, 4 H),2.60-2.91 (m, 3 H), 2.02-2.33 (m, 1 H), 1.68- 1.97 (m, 4 H), 1.58-1.68(m, 1 H), 1.46-1.57 (m, 1 H), 1.32-1.45 (m, 1 H) Apiperidinyl)carbonyl)-N-((1S)-2,2,2-trifluoro-1-(3-fluoro-4-methoxyphenyl)ethyl)-D-prolinamide 777

LCMS-ESI (POS.) m/z: 566.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) 6 ppm 8.72(br s, 1 H), 7.42-7.94 (m, 7 H), 4.46-4.65 (m, 1 H), 4.06-4.26 (m, 1 H),3.12- 3.67 (m, 2 H), 2.10-2.29 (m, 1 H), 1.65-1.91 (m, 3 H), 0.90-1.22(m, 1 H), 0.03-0.69 (m, 4 H) C1-(2-chloro-4-fluoro-5-sulfamoylbenzoyl)-N-((R)- cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide 778

LCMS- APCI (NEG.) m/z: 507.1 (M − H) 1H NMR (400 MHz, Methanol-d4) δ ppm7.93- 8.07 (m, 2 H), 7.72-7.91 (m, 2 H), 7.60-7.67 (m, 2 H), 7.42-7.58(m, 2 H), 5.05-5.17 (m, 1 H), 4.43- 4.60 (m, 2 H), 4.04-4.17 (m, 2 H),3.85-3.98 (m, 2 H), 3.43-3.60 (m, 1 H), 2.96-3.09 (m, 3 H), 1.42- 1.63(m, 3 H). Q 3-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-((1S)-1-methyl-2-oxo-2-((4-(trifluoromethyl)benzyl)amino)ethyl)benzamide 779

(1S,3R,5S)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 510.0 (M +H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.84-8.93 (m, 1 H), 8.36- 8.48(m, 1 H), 7.74-7.87 (m, 1 H), 7.28-7.35 (m, 1 H), 7.10-7.20 (m, 2 H),4.73 (dd, J = 8.55, 3.06 Hz, 1 H), 4.47 (t, J = 7.83 Hz, 1 H), 3.29 (s,3 H), 3.15- 3.23 (m, 1 H), 2.76 (ddd, J = 13.48, 7.26, 2.90 Hz, 1 H),1.99-2.15 (m, 2 H), 1.18-1.30 (m, 1 H), 1.11 (dt, J = 8.86, 5.52 Hz, 1H), 0.76 (td, J = 5.11, 2.54 Hz, 1 H), 0.63-0.73 (m, 1 H), 0.59 (tt, J =8.60, 4.41 Hz, 1 H), 0.33-0.52 (m, 2 H) C 780

1-(((3S)4-(cyclobutylsulfonyl)-3- piperidinyl)carbonyl)-N-(4- LCMS- APCI(POS.) m/z: 502.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δ ppm 7.64 (d,J = 8.1 Hz, 2 H), 7.50 (d, J = 7.9 Hz, 2 H), 4.48 (d, J = 2.2 Hz, 2 H),4.44 (dd, J = 4.4, 8.3 Hz, 1 H), 3.93-4.03 (m, 1 H), 3.70- 3.77 (m, 3H), 2.73-2.83 (m, 2 H), 2.43-2.53 (m, 3 H), 2.24-2.37 (m, 4 H),1.94-2.12 (m, 7 H), 1.50- 1.65 (m, 2 H). R(trifluoromethyl)benzyl)-D-prolinamide 781

LCMS-ESI (POS.) m/z: 526.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.29- 8.71 (m, 1 H), 6.96-7.43 (m, 4 H), 4.24-4.55 (m, 3 H), 3.88-4.13(m, 4 H), 3.41-3.84 (m, 6 H), 2.61- 2.87 (m, 3 H), 2.06-2.34 (m, 1 H),1.34-2.00 (m, 7 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3- (difluoromethoxy)benzyl)-D-prolinamide 782

1-(((3S)-1-((3-(acetylamino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 560.2 (M +H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 7.82- 8.91 (m, 2 H), 7.35-7.81 (m, 1H), 6.86-7.35 (m, 1 H), 4.38-4.59 (m, 1 H), 4.26-4.37 (m, 2 H), 4.04-4.26 (m, 5 H), 3.86-4.04 (m, 2 H), 3.59-3.73 (m, 2 H), 3.53-3.59 (m, 1H), 3.27-3.49 (m, 1 H), 2.62- 2.84 (m, 2 H), 2.00-2.15 (m, 1 H),1.67-1.99 (m, 4 H), 1.30-1.63 (m, 1 H) M 783

LCMS-ESI (POS.) m/z: 532.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.04- 8.74 (m, 1 H), 6.53-6.84 (m, 3 H), 4.81-5.04 (m, 1 H), 4.21-4.46(m, 1 H), 3.41-4.19 (m, 13 H), 2.59 -2.87 (m, 3 H), 1.65-2.33 (m, 9 H),1.31-1.57 (m, 2 H) A 1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4R)-6-methoxy-3,4-dihydro-2H-chromen-4-yl)-D-prolinamide 784

LCMS-ESI (POS.) m/z: 465.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.42- 8.65 (m, 1 H), 6.66-7.71 (m, 8 H), 4.18-4.57 (m, 2 H), 3.66-3.76(m, 3 H), 3.42-3.56 (m, 1 H), 2.00- 2.16 (m, 1 H), 1.55-1.81 (m, 3 H),0.89-1.17 (m, 1 H), 0.00-0.56 (m, 4 H) C N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3- methoxybenzoyl)-D-prolinamide 785

LCMS-ESI (POS.) m/z: 467.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.77-7.99 (m, 2 H), 7.60- 7.77 (m, 2 H), 7.29-7.41 (m, 4 H), 7.14-7.27(m, 2 H), 5.11 (quin, J = 7.23 Hz, 1 H), 4.75-4.87 (m, 1 H), 4.73-6.10(m, 1 H), 3.97- 4.22 (m, 4 H), 3.27-3.94 (m, 3 H), 1.80-2.59 (m, 4 H),1.41-1.57 (m, 3 H) A 1-((3-((3-cyano-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((1R)-1-phenylethyl)-D-prolinamide 786

(1R,3R,5R)-2((4-ethyl-2-pyridinyl)carbonyl)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS- APCI(POS.) m/z: 492.2 (M + H)⁺ 1H NMR (DMSO-d6) δ: 8.71 (d, J = 8.1 Hz, 1H),8.52 (dd, J = 5.0, 0.8 Hz, 1H), 8.46 (d, J = 8.3 Hz, 1H), 8.33 (dd, J =5.0, 0.8 Hz, 1H), 7.74-7.53 (m, 5H), 7.45 (t, J = 7.6 Hz, 1H), 7.39 (dd,J = 5.0, 1.8 Hz, 1H), 7.33 (dd, J = 5.0, 1.8 Hz, 1H), 5.56-5.44 (m, 2H),5.19 (t, J = 9.0 Hz, 1H), 4.86 (d, J = 11.4, 3.4 Hz, 1H), 4.75-4.62 (m,1H), 4.58-4.50 (m, 1H), 4.45 (t, J = 6.1 Hz, 1H), 4.38 (dd, J = 7.8, 6.2Hz, 2H), 4.26 (t, J = 6.1 Hz, 1H), 3.97 (td, J = 6.3, 2.6 Hz, 1H), 3.90(t, J = 6.2 Hz, 1H), 3.85 (t, J = 6.1 Hz, 1H), 3.81-3.75 (m, 1H),3.49-3.38 (m, 1H), 3.29-3.17 (m, 1H), 2.69 (dq, J = 15.0, 7.6 Hz, 4H),1.77 (dd, J = 13.4, 2.8 Hz, 1H), 1.69 (dd, J = 13.5, 3.2 Hz, 1H), 1.60(d, J = 8.7 Hz, 1H), 1.51 (p, J = 6.2 Hz, 1H), 1.21 (dt, J = 9.7, 7.6Hz, 6H), 1.08-1.01 (m, 1H), 0.71 (dd, J = 6.4, 4.1 Hz, 2H), 0.65-0.51(m, 1H) Q 787

LCMS-ESI (POS.) m/z: 585.2 (M + Na)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.28- 8.75 (m, 1 H), 7.61-7.74 (m, 2 H), 7.45 (br d, J = 7.27 Hz, 2 H),4.26-4.53 (m, 3 H), 3.84-3.96 (m, 2 H), 3.51-3.67 (m, 6 H), 2.70- 2.90(m, 3 H), 2.53-2.68 (m, 3 H), 1.33-2.39 (m, 9 H) M1-(((3S)-1-((3-(2,2,2-trifluoroethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 788

1-(((3S)-1((3-(methoxymethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide LCMS-ESI (POS.) m/z: 547.2 (M +H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (d, J = 8.04 Hz, 2 H),7.49 (br t, J = 5.06 Hz, 1 H), 7.33-7.42 (m, 3 H), 4.61 (dd, J = 7.79,1.56 Hz, 1 H), 4.38-4.54 (m, 2 H), 3.93 (t, J = 8.04 Hz, 2 H), 3.73-3.84 (m, 2 H), 3.67 (ddd, J = 7.91, 5.71, 2.72 Hz, 2 H), 3.55-3.62 (m, 2H), 3.52 (d, J = 6.75 Hz, 2 H), 3.37 (s, 3 H), 2.92 (dd, J = 12.33,11.29 Hz, 1 H), 2.65-2.86 (m, 3 H), 2.41-2.61 (m, 1 H), 2.11-2.24 (m, 1H), 1.99-2.10 (m, 1 H), 1.81- 1.94 (m, 3 H), 1.74-1.81 (m, 1 H),1.46-1.72 (m, 4 H) M 789

(1R,3R,5R)-N-((R)-(2-fluoro-4-(trifluoromethyl)phenyl)(3-oxetanyl)methyl)-2-((6-(trifluoromethyl)-2-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS- APCI (POS.) m/z: 532.1 (M +H)⁺ 1H NMR (Methanol-d4) δ: 8.27-8.16 (m, 2H), 8.13 (t, J = 7.4 Hz, 1H),7.97 (d, 1H), 7.91 (dd, J = 7.6, 1.3 Hz, 1H), 7.61-7.51 (m, 3H),7.51-7.43 (m, 2H), 7.37 (t, J = 7.7 Hz, 1H), 5.78 (dd, J = 11.7, 2.9 Hz,1H), 5.66 (d, J = 10.2 Hz, 1H), 5.26 (d, J = 10.4 Hz, 1H), 4.99 (dd, J =11.3, 3.8 Hz, 1H), 4.74-4.62 (m, 2H), 4.59-4.46 (m, 1H), 4.47-4.37 (m,1H), 4.07- 3.96 (m, 2H), 3.95-3.82 (m, 2H), 3.66-3.52 (m, 1H), 2.96-2.82(m, 1H), 2.66 (td, J = 12.6, 6.5 Hz, 1H), 2.09-1.95 (m, 1H), 1.95-1.86(m, 2H), 1.86- 1.73 (m, 1H), 1.71-1.62 (m, 1H), 1.57 (d, J = 6.8 Hz,1H), 1.37-1.21 (m, 3H), 1.16 (td, J = 5.4, 2.6 Hz, 1H), 0.98-0.81 (m,2H), 0.81-0.72 (m, 1H), 0.71-0.61 (m, 1H) Q 790

LCMS-ESI (POS.) m/z: 529.0 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ8.28-8.78 (m, 1H), 8.03-8.25 (m, 1H), 7.30-7.61 (m, 1H), 7.22- 7.25 (m,1H), 4.22-4.39 (m, 3H), 4.01-4.14 (m, 2H), 3.88-3.98 (m, 2H), 3.70- 3.88(m, 2H), 3.30-3.62 (m, 6H), 2.91-3.06 (m, 1H), 2.68-2.78 (m, 2H), 1.74-2.16 (m, 4H) E 1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(3,5-dichlorobenzyl)-D- prolinamide 791

(5S)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-5-methyl-1-(3- LCMS-ESI (POS.) m/z:527.2 (M + H)⁺ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.98 (br s, 2 H),7.54-7.85 (m, 2 H), 7.29-7.49 (m, 3 H), 7.22-7.27 (m, 1 H), 4.31-4.84(m, 2 H), 4.02- 4.25 (m, 1 H), 3.00-3.15 (m, 3 H), 2.33-2.49 (m, 1 H),1.84-2.29 (m, 2 H), 1.63-1.71 (m, 1 H), 0.82- 1.42 (m, 4 H), − 0.05-0.63(m, 4 H) C (methylsulfonyl)benzoyl)-D-prolinamide 792

(4S)-N-((R)-cyclopropyl(3-fluoro-4- methylphenyl)methyl)-4-fluoro-1-(3-LCMS- APCI (NEG.) m/z: 475.1 (M − H) 1H NMR (400 MHz, DMSO-d6) δ ppm8.66 (d, J = 8.3 Hz, 1 H), 7.88- 8.12 (m, 1 H), 7.69-7.82 (m, 1 H),6.87-7.25 (m, 2 H), 5.33 (dd, J = 18.5, 52.7 Hz, 1 H), 4.26-4.74 (m, 2H), 3.95 (dd, J = 13.2, 37.8 Hz, 1 H), 3.60 (dd, J = 12.7, 20.1 Hz, 1H), 3.29 (d, J = 5.1 Hz, 1 H), 2.19 (d, 1 H), 1.86-2.09 (m, 1 H),0.47-0.80 (m, 1 H), 0.33-0.46 (m, 1 H), −0.34- 0.06 (m, 1 H). A(methylsulfonyl)benzoyl)-D-prolinamide 793

LCMS-ESI (POS.) m/z: 469.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.41- 8.71 (m, 1 H), 7.13-8.14 (m, 8 H), 4.38-4.40 (m, 1 H), 4.07-4.52(m, 2 H), 3.41-3.71 (m, 2 H), 3.34- 3.39 (m, 1 H), 3.19-3.28 (m, 1 H),2.17-2.35 (m, 1 H), 1.73-1.99 (m, 3 H), 0.93-1.17 (m, 3 H) C1-(3-(ethylsulfonyl)benzoyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 794

LCMS-ESI (POS.) m/z: 493.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.40- 8.74 (m, 1 H), 7.41-7.74 (m, 5 H), 6.53-7.40 (m, 2 H), 5.02-5.12(m, 1 H), 4.25-4.63 (m, 2 H), 3.37- 3.64 (m, 2 H), 2.11-2.22 (m, 1 H),1.64-1.88 (m, 3 H), 1.37-1.47 (m, 6 H), 0.98-1.25 (m, 1 H), 0.05- 0.62(m, 4 H) C N-((R)-cyclopropyl(2-fluoro-4-2-propanyl)benzoyl)-D-prolinamide(trifluoromethyl)phenyl)methyl)-1-(3-(2-hydroxy- 795

(1R,3R,5R)-N-((R)-(4-chloro-3- fluorophenyl)(cyclopropyl)methyl)-2-((2-(methylsulfonyl)-4-pyridinyl)carbonyl)-2- LCMS-ESI (POS.) m/z: 492.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.28- 9.00 (m, 2 H), 7.69-8.22(m, 2 H), 7.49-7.62 (m, 1 H), 7.01-7.46 (m, 2 H), 4.59-5.02 (m, 1 H),3.80- 4.31 (m, 1 H), 3.26-3.34 (m, 4 H), 2.57-2.70 (m, 1 H), 1.56 (s, 2H), 0.69- 1.29 (m, 3 H), − 0.32-0.56 (m, 4 H) Cazabicyclo[3.1.0]hexane-3-carboxamide 796

LCMS- APCI (POS.) m/z: 550.2 (M + H)⁺ 1H NMR (400 MHz, Methanol-d4) δppm 7.17- 7.61 (m, 7 H), 3.91-4.54 (m, 6 H), 3.27-3.55 (m, 2 H),1.61-2.19 (m, 7 H), 1.05-1.17(m, 1 H), 0.20- 0.56(m,4 H). W1-(3-(1-acet-3-fluoro-3-azetidinyl)benzoyl)-N-((R)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide 797

(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-((5-methyl-3-pyridinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide LCMS- APCI(POS.) m/z: 480.2 (M + H)⁺ 1H NMR (Methanol-d4) δ: 8.64 (s, 1H), 8.42(s, 1H), 7.91 (s, 1H), 7.40 (dd, J = 9.5, 5.7 Hz, 1H), 7.32 (dd, J =10.8, 5.6 Hz, 1H), 4.93 (dd, J = 11.4, 4.0 Hz, 1H), 4.39 (d, J = 9.0 Hz,1H), 2.66-2.51 (m, 1H), 2.33 (s, 3H), 1.82 (dd, J = 13.5, 4.0 Hz, 1H),1.74-1.62 (m, 1H), 1.19-1.11 (m, 1H), 1.06 (td, J = 5.3, 2.6 Hz, 1H),0.75 (dt, J = 9.1, 5.8 Hz, 2H), 0.64-0.54 (m, 1H), 0.53-0.44 (m, 1H),0.44-0.31 (m, 2H) Q 798

LCMS-ESI (POS.) m/z: 547.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68(br s, 2 H), 7.67-8.04 (m, 6 H), 5.18* (br s, 1 H), 4.02- 4.56 (m, 7 H),3.17-3.39 (m, 2 H), 2.75-2.91* (m, 2 H), 2.25 (br d, J = 10.11 Hz, 1 H),1.21-1.80 (m, 5 H). Spectrum appears as 2:1 mixture of rotamers,*denotes resolved minor rotamer peaks. C (2R)-1-((3-((3,3-difluoro-1-azetidinyl)sulfonyl)phenyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-2- piperidinecarboxamide 799

(2R)-1-((S)-1-((3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(2- LCMS-ESI (POS.) m/z: 492.2 (M +H)⁺ 1H NMR (600 MHz, DMSO-d6) δ ppm 7.98- 8.62 (m, 1 H), 4.35-4.45 (m, 1H), 4.24-4.34 (m, 1 H), 4.01-4.19 (m, 1 H), 3.99-4.46 (m, 2 H), 3.86-3.96 (m, 2 H), 3.74-3.84 (m, 1 H), 3.49-3.68 (m, 3 H), 3.27-3.34 (m, 1H), 2.96-3.17 (m, 1 H), 2.56- 2.92 (m, 3 H), 1.92-2.23 (m, 3 H),1.83-1.91 (m, 4 H), 1.58-1.75 (m, 3 H), 1.28-1.53 (m, 2 H) A(trifluoromethyl)cyclobutyl)pyrrolidine-2- carboxamide 800

LCMS-ESI (POS.) m/z: 543.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.31- 8.80 (m, 1 H), 7.57-7.76 (m, 2 H), 7.45 (br d, J = 8.04 Hz, 2 H),4.21-4.56 (m, 3 H), 3.52-3.70 (m, 6 H), 2.61-2.84 (m, 3 H), 1.29- 2.41(m, 16 H) M 1-(((3S)-1-(1-azaspiro[3.3]hept-1-ylsulfonyl)-3-piperidinyl)carbonyl)-N-(4- (trifluoromethyl)benzyl)-D-prolinamide 801

LCMS-ESI (POS.) m/z: 540.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.33-7.76 (m, 4 H), 7.22- 7.29 (m, 1 H), 4.39-4.66 (m, 3 H), 4.03-4.18(m, 4 H), 3.70-3.88 (m, 2 H), 3.24-3.53 (m, 2 H), 3.01- 3.13 (m, 1 H),2.90-3.01 (m, 1 H), 2.74-2.90 (m, 2 H), 1.50-2.17 (m, 5 H), 1.32-2.23(m, 1 H), 0.52- 1.26 (m, 2 H) C (1R,3S,5R)-2-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide 802

LCMS-ESI (POS.) m/z: 542.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.51- 8.71 (m, 1 H), 7.31-7.88 (m, 7 H), 4.28-4.65 (m, 2 H), 3.41-3.73(m, 2 H), 2.51-2.70(m, 6 H), 2.19- 2.34 (m, 1 H), 1.73-1.99 (m, 3 H),1.15-1.23 (m, 1 H), 0.15-0.61 (m, 4 H) A N-((S)-cyclopropyl(2-fluoro-4-(trifluoromethyl)phenyl)methyl)-1-(3-(dimethylsulfamoyl)benzoyl)-D-prolinamide 803

N-((1S)-1-(4-chlorophenyl)ethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- piperidinyl)carbonyl)-D-prolinamideLCMS-ESI (POS.) m/z: 508.2 (M + H)⁺ 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.28-7.50 (m, 2 H), 7.15- 7.19 (m, 2 H), 4.95-5.04 (m, 1 H), 4.60 (br d,J = 6.36 Hz, 1 H), 4.06-4.16 (m, 4 H), 3.77 (br d, J = 12.46 Hz, 2 H),3.40-3.66 (m, 3 H), 2.93-3.02 (m, 1 H), 2.63- 2.85 (m, 3 H), 2.39-2.45(m, 1 H), 2.11-2.21 (m, 1 H), 1.97-2.05 (m, 1 H), 1.79-1.95 (m, 3 H),1.48- 1.69 (m, 2 H), 1.45 (d, J = 6.88 Hz, 3 H) C 804

(2R)-1-((S)-1-( (3-cyanoazetidin-1-yl)sulfonyl)piperidine-3-carbonyl)-N-(1-(2- LCMS-ESI (POS.) m/z: 518.2(M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 7.85- 8.45 (m, 1 H), 7.11-7.31(m, 2 H), 6.81-7.04 (m, 2 H), 4.93-5.08 (m, 1 H), 4.31-4.52 (m, 1 H),3.89- 4.14 (m, 4 H), 3.74-3.88 (m, 4 H), 3.44-3.69 (m, 4 H), 2.59-2.91(m, 3 H), 2.00-2.37 (m, 1 H), 1.19- 1.97 (m, 9 H), 0.71-0.94 (m, 3 H) Amethoxyphenyl)propyl)pyrrolidine-2-carboxamide 805

1-(4-amino-3-(methylsulfonyl)benzoyl)-N-((R)- cyclopropyl(2-fluoro-4-LCMS-ESI (POS.) m/z: 528.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.63(br d, J = 5.97 Hz, 1 H), 7.24- 7.89 (m, 5 H), 6.89 (br d, J = 7.66 Hz,1 H), 6.27- 6.62 (m, 2 H), 4.19-4.66 (m, 2 H), 3.54-3.65 (m, 2 H),3.09-3.20 (m, 3 H), 2.07-2.25 (m, 1 H), 1.56- 1.95 (m, 3 H), 0.94-1.30(m, 1 H),-0.02-0.62 (m, 4 H) C(trifluoromethyl)phenyl)methyl)-D-prolinamide 806

LCMS-ESI (POS.) m/z: 560.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ8.28-8.80 (m, 1H), 7.59-8.03 (m, 3H), 7.34-7.55 (m, 2H), 4.21- 4.53 (m,4H), 3.87-4.12 (m, 3H), 3.41-3.75 (m, 6H), 2.55-2.73 (m, 3H), 1.74- 2.35(m, 8H), 1.26-1.59 (m, 2H) J1-(((3S)-1-((1-acet-3-azetidinyl)sulfamo)-3- piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide 807

LCMS-ESI (POS.) m/z: 512.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.27- 8.62 (m, 1 H), 7.42-8.11 (m, 7 H), 4.38-4.97 (m, 2 H), 3.39-3.65(m, 2 H), 3.21-3.29 (m, 3 H), 2.11- 2.29 (m, 1 H), 1.57-2.07 (m, 4 H),0.48-1.08 (m, 6 H) C N-((lR)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-1-(3-(methylsulfonyl)benzoyl)-D- prolinamide 808

(1R,3R,5R)-2-(2-methoxy-5- (methylsulfonyl)benzoyl)-N-((R)-3-oxetanyl(4-(trifluoromethyl)phenyl)methyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS- APCI (POS.) m/z: 553.1 (M + H)⁺ 1H NMR (400 MHz, Chloroform-d) δppm 8.01 -8.07 (m, 3 H), 7.71 (s, 1 H), 7.61 (d, 2 H), 7.39 (d, J = 7.8Hz, 2 H), 7.16 (d, 1 H), 5.42 (t, J = 8.3 Hz, 1 H), 5.12 (d, J = 10.5Hz, 1 H), 4.66-4.76 (m, 2 H), 4.60 (t, J = 6.4 Hz, 1 H), 4.45 (t, J =6.4 Hz, 1 H), 4.14 (q, J = 7.1 Hz, 1 H), 3.99 (s, 3 H), 3.45 (tdd, J =1.7, 6.2, 8.0 Hz, 1 H), 3.09 (s, 5 H), 2.80 (dd, J = 2.0, 13.2 Hz, 1 H),2.27-2.36 (m, 1 H), 2.07 (s, 1 H), 1.68 (dd, J = 5.3, 9.2 Hz, 1 H), 1.28(t, J = 7.1 Hz, 1 H), 0.85-0.95 (m, 1 H), 0.72-0.80 (m, 1 H). S 809

LCMS-ESI (POS.) m/z: 514.0 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm8.19- 9.25 (m, 4 H), 7.21-7.91 (m, 3 H), 4.26-4.67 (m, 2 H), 3.46-3.67(m, 2 H), 3.25-3.45 (m, 3 H), 2.10- 2.31 (m, 1 H), 1.65-2.00 (m, 3 H),0.98-0.99 (m, 1 H), 0.87-1.32 (m, 1 H), − 0.15-0.65 (m, 4 H) C(2R)-N-(cyclopropyl(2-fluoro-4- (trifluoromethyl)phenyl)methyl)-1-(5-(methylsulfonyl)nicotinoyl)pyrrolidine-2- carboxamide 810

(1R,3R,5R)-N-((R)-cyclopropyl(3-fluoro-4- methylphenyl)methyl)-2-(3-(methylsulfonyl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide LCMS-APCI (POS.) m/z: 471.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (d,J = 8.2 Hz, 1 H), 8.19 (t, J = 1.7 Hz, 1 H), 7.98-8.10 (m, 2 H), 7.79(t, J = 7.8 Hz, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 7.04-7.13 (m, 1 H),4.95 (dd, J = 3.6, 11.4 Hz, 1 H), 4.35 (t, J = 5.1 Hz, 1 H), 4.26 (t, J= 8.1 Hz, 1 H), 3.26 (d, J = 6.1 Hz, 2 H), 2.14-2.24 (m, 2 H), 1.63-1.81(m, 2 H), 1.11 (dd, J = 4.8, 8.3 Hz, 1 H), 0.71-0.80 (m, 1 H), 0.36-0.51(m, 2 H), 0.23- 0.34 (m, 1 H). C 811

1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3- LCMS-ESI (POS.) m/z:542.1 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 7.38- 8.23 (m, 5 H),4.15-4.38 (m, 1 H), 3.99-4.11 (m, 2 H), 3.86-3.99 (m, 2 H), 3.74-3.84(m, 1 H), 3.14- 3.67 (m, 6 H), 2.63-2.92 (m, 1 H), 2.51-2.96 (m, 3 H),2.50-2.99 (m, 1 H), 1.97-2.30 (m, 1 H), 1.59- 1.91 (m, 5 H), 1.28-1.57(m, 2 H) A piperidinyl)carbonyl)-N-(2-(4-(trifluoromethyl)phenyl)ethyl)-D- prolinamide 812

(1R,3R,5R)-N-((S)-(4-Chloro-2,5-difluorophenyl)(3-fluorooxetan-3-yl)methyl)-2-(3- LCMS-ESI (POS.) m/z:543.1 (M + H)⁺ 1H NMR (Methanol-d4) δ: 8.39 (s, 1H), 8.16-8.10 (m, 2H),7.79 (t, J = 7.8 Hz, 1H), 7.46 (dd, J = 9.3, 6.1 Hz, 1H), 7.39 (dd, J =9.7, 6.3 Hz, 1H), 5.98 (d, J = 28.0 Hz, 1H), 5.05 (dd, J = 11.4, 4.3 Hz,1H), 4.82- 4.74 (m, 2H), 4.65-4.55 (m, 2H), 3.33 (s, 1H), 3.19 (s, 3H),2.77-2.63 (m, 1H), 1.95-1.86 (m, 1H), 1.86-1.77 (m, 1H), 1.34- 1.27 (m,1H), 0.97-0.88 (m, 1H) Y (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide 813

(1R,3R,5R)-2-(2-amino-5-(methylsulfonyl)benzoyl)-N-((R)-cyclopropyl(2-fluoro-4- (trifluoromethyl)phenypmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 540.2 ¹H NMR(Methanol-d₄) δ: 7.85 (s, 1H), 7.57 (dd, J = 8.7, 2.3 Hz, 2H), 7.47-7.32 (m, 2H), 6.77 (d, J = 8.8 Hz, 1H), 5.00 (dd, J = 11.5, 3.5 Hz, 1H),4.47 (d, J = 8.9 Hz, 1H), 3.21-3.15 (m, 1H), 2.97 (s, 3H), 2.67- 2.57(m, 1H), 1.85 (dd, J = 13.6, 3.5 Hz, 1H), 1.65- 1.55 (m, 1H), 1.25-1.14(m, 1H), 0.97-0.90 (m, 1H), 0.71-0.63 (m, 1H), 0.63-0.54 (m, 1H), 0.52-0.45 (m, 1H), 0.45-0.38 (m, 1H), 0.38-0.26 (m, 1H) AA 814

(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenypmethyl)-2-(2-(hydroxymethyl)-5-(methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 571.2 (M −H)⁺ ¹H NMR (DMSO-d₆) δ: 8.76 (d, J = 7.4 Hz, 1H), 8.00 (dd, J = 8.1, 2.0Hz, 1H), 7.88 (d, J = 1.9 Hz, 1H), 7.86-7.74 (m, 2H), 7.59 (dd, J =11.1, 5.5 Hz, 1H), 5.64 (t, J = 5.7 Hz, 1H), 4.89 (dd, J = 11.4, 3.2 Hz,1H),4.71 (qd, J = 15.1, 5.8 Hz, 2H), 4.54 (t, J = 8.0 Hz, 1H), 3.25 (s,3H), 3.00 (td, J = 6.2, 2.5 Hz, 1H), 1.80 (dd, J = 13.5, 3.3 Hz, 1H),1.67-1.54 (m, 1H), 1.21 (dq, J = 8.2, 4.1, 3.5 Hz, 1H), 0.97 (td, J =5.2, 2.7 Hz, 1H), 0.59 (t, J = 8.5 Hz, 2H), 0.55-0.45 (m, 1H), 0.40 (d,J = 4.8 Hz, 2H) Z 815

(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(2-methoxyisonicotinoyl)-2-azabicyclo[3.1.0]hexane- 3-carboxamide LCMS-ESI(POS.) m/z: 512.2 ¹H NMR (Methanol-d₄) δ: 8.27 (dd, J = 5.2, 0.8 Hz,1H), 7.56 (dd, J = 9.5, 5.7 Hz, 1H), 7.37 (dd, J = 10.6, 5.5 Hz, 1H),7.24 (dd, J = 5.2, 1.3 Hz, 1H), 7.09 (s, 1H), 5.62 (d, J = 10.2 Hz, 1H),4.94 (dd, J = 11.4, 4.0 Hz, 1H), 4.85 (dd, J = 7.6, 6.5 Hz, 1H), 4.68(t, J = 7.8, 6.5 Hz, 1H), 4.61 (t, J = 6.2 Hz, 1H), 4.40 (t, 1H), 3.97(s, 3H), 3.62-3.46 (m, 1H), 3.31-3.26 (m, 1H), 2.74-2.58 (m, 1H), 1.90(dd, J = 13.5, 4.0 Hz, 1H), 1.85-1.72 (m, 1H), 1.24-1.16(m, 1H), 0.90-0.78 (m, 1H) AA 816

(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(5-methylthiophene-2-carbonyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS-ESI (POS.) m/z: 501.1 ¹H NMR (Methanol-d₄) δ: 7.72 (d, J = 3.8 Hz,1H), 7.54 (dd, J = 9.5, 5.7 Hz, 1H), 7.36 (dd, J = 10.6, 5.5 Hz, 1H),6.91-6.84 (m, 1H), 5.57 (d, J = 10.3 Hz, 1H), 4.96 (dd, J = 11.2, 4.6Hz, 1H), 4.85 (t, J = 7.0 Hz, 1H), 4.70-4.59 (m, 2H), 4.39 (t, J = 6.2Hz, 1H), 3.80-3.69 (m, 1H), 3.58-3.42 (m, 1H), 2.73- 2.57 (m, 1H), 2.54(s, 3H), 1.93-1.74 (m, 2H), 1.26- 1.16 (m, 1H), 1.05-0.93 (m, 1H) AA 817

(1R,3R,5R)-N-((S)-1-(4-chloro-2,5-difluorophenyl)-2,2-difluoroethyl)-2-(5-(methylsulfonypnicotinoyl)- LCMS-ESI (POS.) m/z:520.1 ¹H NMR (DMSO-d₆) δ: 9.22 (d, J = 2.3 Hz, 1H), 9.20-9.14 (m, 2H),8.51 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 9.3, 6.2 Hz, 1H), 7.59 (dd, J =9.7, 6.2 Hz, 1H), 6.31 (td, J = 54.9, 3.6 Hz, 1H), 5.63-5.41 (m, 1H),5.04 (dd, J = 11.4, 3.6 Hz, 1H), 3.41 (s, 4H), 2.72- 2.58 (m, 1H),1.84-1.69 (m, 2H), 1.11 (td, J = 5.2, 2.6 Hz, 1H), 0.80 (ddd, J = 11.4,7.8, 4.7 Hz, 1H) AB 2-azabicyclo[3.1.0]hexane-3-carboxamide 818

(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(1,4-dimethyl-1H-pyrazole-5-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 499.2 ¹H NMR(Methanol-d₄) δ: 7.44 (dd, J = 9.6, 5.7 Hz, 1H), 7.26 (dd, J = 10.6, 5.5Hz, 1H), 7.23 (s, 1H), 5.59- 5.44 (m, 1H), 4.87 (dd, J = 11.5, 3.6 Hz,1H), 4.74- 4.71 (m, 1H), 4.57 (t, J = 7.8, 6.5 Hz, 1H), 4.50 (t, J = 6.2Hz, 1H), 4.31-4.26 (m, 1H), 3.79 (s, 3H), 3.51- 3.31 (m, 1H), 3.12 (td,J = 6.3, 2.6 Hz, 1H), 2.63- 2.47 (m, 1H), 2.07 (s, 3H), 1.98 (s, 1H),1.80 (dd, J = 13.5, 3.6 Hz, 1H), 1.67- 1.54 (m, 1H), 1.14-1.04 (m, 1H),0.74-0.62 (m, 1H) AA 819

(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3-(2-hydroxypropan-2-yl)benzoyl)-2- azabicyclo[3.1.0]hexane-3-carboxamideLCMS-ESI (POS.) m/z: 539.2 ¹H NMR (Methanol-d₄) δ: 7.94 (s, 1H),7.70-7.59 (m, 2H), 7.56 (dd, J = 9.6, 5.7 Hz, 1H), 7.45 (t, J = 7.8, 0.5Hz, 1H), 7.38 (dd, J = 10.5, 5.5 Hz, 1H), 5.62 (d, J = 10.2 Hz, 1H),4.99 (dd, J = 11.4, 4.2 Hz, 1H), 4.85 (t, J = 7.7, 6.6 Hz, 1H), 4.68 (t,J = 7.8, 6.5 Hz, 1H), 4.62 (t, J = 6.2 Hz, 1H), 4.45-4.35 (m, 1H),3.62-3.44 (m, 1H), 2.71-2.58 (m, 1H), 1.92 (dd, J = 13.5, 4.1 Hz, 1H),1.83-1.71 (m, 1H), 1.58 (d, J = 2.0 Hz, 7H), 1.28- 1.16 (m, 1H),0.93-0.80 (m, 1H) AC 820

(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(5- LCMS-ESI (POS.) m/z:535.2 (M + H)⁺ 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.74 (d, J =7.9 Hz, 1H), 8.05 (s, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.75-7.50 (m, 3H),5.49 (t, J = 8.8 Hz, 1H), 5.00 (d, J = 11.4 Hz, 1H), 4.66 (s, 1H), 4.53(s, 1H), 4.41 (s, 1H), 4.25 (s, 1H), 3.44 (s, 1H), 2.61 (s, 1H), 2.46(s, 3H), 2.37 (s, 1H), 1.88-1.61 (m, 2H), 1.13 (s, 1H), 0.78 (s, 1H). AAmethyl-1H-indazole-7-carbonyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide821

(1R,3R,5R)-2-(5-chloro-1H-indazole-7-carbonyl)-N-((R)-cyclopropyl(2,5-difluoro-4- (trifluoromethyl)phenyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 539.2 (M +H)⁺ 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 8.76 (d, J = 7.4 Hz, 1H),8.26-7.97 (m, 2H), 7.86- 7.57 (m, 3H), 5.04 (dd, J = 3.5, 11.4 Hz, 1H),4.55 (t, J = 7.9 Hz, 1H), 2.77-2.56 (m, 1H), 1.74 (ddd, J = 4.6, 11.1,31.9 Hz, 2H), 1.33- 1.12 (m, 1H), 1.07 (dt, J = 3.4, 7.2 Hz, 1H), 1.00-0.68 (m, 2H), 0.67-0.55 (m, 1H), 0.47 (t, J = 9.0 Hz, 1H), 0.38 (d, J =4.0 Hz, 2H). AA 822

(1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(5-(1-hydroxyethyl)-2-methylisonicotino)-2- LCMS-ESI (POS.) m/z: 524.2 ¹H NMR(Methanol-d₄) δ: 8.61 (s, 1H), 7.55-7.41 (m, 2H), 7.31 (s, 1H), 5.24-5.12 (m, 1H), 4.94 (ddd, J = 11.3, 3.2, 1.5 Hz, 1H), 4.50 (d, J = 9.1Hz, 1H), 3.09 (td, J = 6.3, 2.7 Hz, 1H), 2.72-2.61 (m, 1H), 2.55 (s,3H), 2.01 (dd, J = 13.5, 3.4 Hz, 1H), 1.76- 1.64 (m, 1H), 1.49 (d, J =6.6 Hz, 3H), 1.26 (tdd, J = 9.5, 6.4, 4.0 Hz, 1H), 1.03 (td, J = 5.4,2.5 Hz, 1H), 0.75-0.63 (m, 2H), 0.63- 0.54 (m, 1H), 0.54-0.41 (m, 2H) ADazabicyclo[3.1.0]hexane-3-carboxamide 823

(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(5-(trifluoromethyl)isoxazole-3-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 540.2 [M + H]1H NMR (Methanol-d4) δ: 7.61-7.50 (m, 1H), 7.46- 7.40 (m, 1H), 7.40-7.26(m, 1H), 5.61 (d, J = 10.2 Hz, 1H), 5.49 (d, 1H), 5.02- 4.92 (m, 1H),4.73-4.55 (m, 2H), 4.41 (t, J = 6.2 Hz, 1H), 4.10 (td, J = 6.3, 2.6 Hz,1H), 3.61-3.42 (m, 1H), 3.37 (s, 2H), 2.75- 2.60 (m, 1H), 1.96-1.75 (m,1H), 1.17 (td, J = 5.5, 2.6 Hz, 1H), 0.96-0.79 (m, 1H) AA 824

(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3,4-dimethylisoxazole-5-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 500.20 [M +H] 1H NMR (DMSO-d6) δ: 8.70 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.6 Hz,1H), 7.55 (t, J = 8.3 Hz, 1H), 5.47 (t, J = 8.9 Hz, 1H), 4.89 (dd, J =11.5, 3.3 Hz, 1H), 4.64 (t, J = 7.7, 6.3 Hz, 1H), 4.52 (t, J = 7.8, 6.3Hz, 1H), 4.37 (t, J = 6.2 Hz, 1H), 4.22 (t, J = 6.2 Hz, 1H), 3.33 (s,3H), 3.32- 3.26 (m, 1H), 2.25 (s, 3H), 1.73 (dd, J = 13.5, 3.4 Hz, 1H),1.66-1.54 (m, 1H), 1.06-0.94 (m, 2H), 0.84-0.68 (m, 2H) AA 825

(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3,5-dimethylisoxazole-4-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 500.2 [M + H]1H NMR (DMSO-d6) δ: 8.70 (d, J = 8.1 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H),7.55 (t, J = 8.2 Hz, 1H), 5.50-5.43 (m, 1H), 4.89 (dd, J = 11.5, 3.3 Hz,1H), 4.64 (t, J = 7.7, 6.4 Hz, 1H), 4.52 (t, J = 7.8, 6.3 Hz, 1H), 4.37(t, J = 6.2 Hz, 1H), 4.22 (t, J = 6.2 Hz, 1H), 3.34 (s, 3H), 3.30- 3.26(m, 1H), 2.25 (s, 3H), 1.73 (dd, J = 13.6, 3.4 Hz, 1H), 1.67-1.52 (m,2H), 1.04-0.96 (m, 1H), 0.85-0.71 (m, 2H) AA 826

(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3-(trifluoromethyl)isoxazole-5-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 540.10 [M +H] 1H NMR (DMSO-d6) δ: 8.77 (t, J = 8.0 Hz, 1H), 7.83-7.72 (m, 2H),7.57- 7.51 (m, 1H), 5.45 (t, 1H), 4.88 (dd, J = 11.4, 3.8 Hz, 1H), 4.66(t, J = 7.7, 6.3 Hz, 1H), 4.61-4.52 (m, 1H), 4.39 (t, J = 6.1 Hz, 1H),4.23 (t, J = 6.1 Hz, 1H), 3.91-3.82 (m, 1H), 3.51-3.36 (m, 2H), 1.82-1.69 (m, 2H), 1.14-1.05 (m, 1H), 0.99-0.90 (m, 1H) AA 827

(R)-N-((R)-(2,5-difluoro-4- (trifluoromethyl)phenyl)((1s,3S)-3-hydroxycyclobutyl)methyl)-1-(3- (methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide LCMS-ESI (POS.) m/z: 561.2 (M + H)⁺ ¹H NMR (DMSO-d₆) δ: 8.51(d, J = 7.9 Hz, 1H), 8.04 (d, J = 1.5 Hz, 2H), 7.93-7.88 (m, 1H), 7.81-7.68 (m, 2H), 7.64 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 11.1, 5.4 Hz, 1H),5.05 (s, 1H), 4.49 (dd, J = 8.3, 5.2 Hz, 1H), 3.87 (q, J = 7.1 Hz, 1H),3.61-3.52 (m, 1H), 3.49-3.44 (m, 1H), 3.28 (s, 3H), 2.35 (dt, J = 12.1,6.2 Hz, 1H), 2.23 (ddd, J = 14.5, 7.4, 4.2 Hz, 1H), 2.11-2.04 (m, 1H),1.84 (dq, J = 20.4, 8.0, 6.8 Hz, 3H), 1.72 (ddt, J = 11.9, 8.4, 4.2 Hz,2H), 1.65- 1.56 (m, 1H) AE 828

(R)-N-((R)-(2,5-difluoro-4- (trifluoromethyl)phenyl)((1r,3R)-3-hydroxycyclobutyl)methyl)-1-(3- (methylsulfonyl)benzoyl)pyrrolidine-2-carboxamide LCMS-ESI (POS.) m/z: 561.2 (M + H)⁺ 1H NMR (Methanol-d4) δ:8.22 (t, J = 1.8 Hz, 1H), 8.10 (dt, J = 7.8, 1.5 Hz, 1H), 7.96 (dt, J =7.6, 1.4 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.53 (dd, J = 9.5, 5.7 Hz,1H), 7.38 (dd, J = 10.7, 5.4 Hz, 1H), 5.21 (d, J = 10.9 Hz, 1H), 4.67-4.54 (m, 1H), 4.44 (dd, J = 9.0, 4.5 Hz, 1H), 3.64 (dt, J = 10.0, 6.8Hz, 1H), 3.54 (ddd, J = 10.4, 6.8, 5.1 Hz, 1H), 2.72 (ddq, J = 13.8,9.1, 4.2 Hz, 1H), 2.44 (ddt, J = 11.4, 7.6, 4.1 Hz, 1H), 2.32 (ddd, J =11.8, 8.2, 5.9 Hz, 1H), 2.18 (ddd, J = 12.4, 8.3, 6.1 Hz, 1H), 2.06(ddd, J = 11.8, 7.8, 4.0 Hz, 1H), 2.02-1.94 (m, 2H), 1.90-1.82 (m, 2H)AE 829

(1R,3R,5R)-N-((R)-(2,5-difluoro-4- (trifluoromethyl)phenyl)(3-hydroxy-3- methylcyclobutyl)methyl)-2-(3- (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 587.2 ¹H NMR(Methanol-d₄) δ: 8.39 (t, J = 1.8 Hz, 1H), 8.12 (ddd, J = 8.0, 3.1, 1.3Hz, 2H), 7.78 (t, J = 7.8 Hz, 1H), 7.52 (dd, J = 9.5, 5.7 Hz, 1H), 7.35(dd, J = 10.7, 5.4 Hz, 1H), 5.06 (dd, J = 11.3, 4.0 Hz, 1H), 3.37 (s,1H), 3.19 (s, 3H), 2.69 (ddd, J = 13.7, 11.5, 6.4 Hz, 1H), 2.29 (dq, J =10.0, 4.3, 3.8 Hz, 2H), 2.03 (dd, J = 14.2, 2.2 Hz, 1H), 1.99- 1.86 (m,3H), 1.81 (dq, J = 9.0, 6.1 Hz, 1H), 1.31 (s, 3H), 1.23 (td, J = 5.4,2.6 Hz, 1H), 0.90 (dt, J = 8.8, 5.7 Hz, 1H) AF 830

(1R,3R,5R)-N-((R)-(2,5-difluoro-4- (trifluoromethyl)phenyl)((1s,3S)-3-hydroxycyclobutyl)methyl)-2-(2- (difluoromethyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 546.2 (M +H)⁺ 1H NMR (DMSO-d6) δ: 8.85 (d, J = 4.9 Hz, 1H), 8.56 (d, J = 7.8 Hz,1H), 7.84 (t, J = 1.1 Hz, 1H), 7.82-7.73 (m, 2H), 7.49 (dd, J = 11.0,5.4 Hz, 1H), 7.07 (t, J = 54.8 Hz, 1H), 5.05-4.94 (m, 2H), 3.85 (q, J =7.2 Hz, 1H), 3.25 (td, J = 6.1, 2.5 Hz, 1H), 2.58 (dt, J = 12.3, 6.2 Hz,1H), 2.38-2.25 (m, 1H), 2.03 (h, J = 7.5, 6.9 Hz, 2H), 1.71 (ddd, J =15.7, 11.3, 4.7 Hz, 2H), 1.63- 1.53 (m, 2H), 1.09 (td, J = 5.1, 2.6 Hz,1H), 0.75- 0.70 (m, 1H) AE 831

(1R,3R,5R)-N-((R)-(2,5-difluoro-4- (trifluoromethyl)phenyl)((1r,3R)-3-hydroxycyclobutyl)methyl)-2-(2- (difluoromethyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z: 546.2 (M +H)⁺ 1H NMR (DMSO-d6) δ: 7.95 (d, J = 4.9 Hz, 1H), 7.14 (s, 1H), 7.01(dd, J = 5.0, 1.3 Hz, 1H), 6.66 (dd, 9.4, 5.8 Hz, 1H), 6.49 (dd, J =10.7, 5.5 Hz, 1H), 5.95 (t, J = 55.1 Hz, 1H), 4.29 (d, J = 10.8 Hz, 1H),4.14 (dd, J = 11.4, 4.0 Hz, 1H), 3.54 (p, J = 6.6 Hz, 1H), 2.42 (td, J =6.2, 2.6 Hz, 1H), 1.82 (ddd, J = 13.6, 11.2, 6.3 Hz, 2H), 1.51 (ddt, J =11.4, 7.5, 3.9 Hz, 1H), 1.29 (ddd, J = 12.7, 8.8, 6.0 Hz, 1H), 1.24-1.07 (m, 2H), 1.07-0.99 (m, 1H), 0.93 (ddd, J = 12.0, 7.4, 4.5 Hz, 1H),0.36 (td, J = 5.4, 2.7 Hz, 1H), −0.01 (dt, J = 9.0, 5.7 Hz, 1H) AE 832

(1R,3R,5R)-N-((S)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(5-oxopyrrolidin-3-yl)methyl)-2-(2-(trifluoromethyl)isonicotinoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide LCMS-ESI (POS.) m/z 546.2 (M + H)⁺1H NMR (DMSO-d6) δ: 8.95 (d, J = 4.9 Hz, 1H), 8.78 (d, J = 8.3 Hz, 1H),8.00 (t, J = 1.1 Hz, 1H), 7.94 (dd, J = 5.0, 1.4 Hz, 1H), 7.80 (dd, J =9.3, 5.8 Hz, 1H), 7.62 (dd, J = 10.9, 5.6 Hz, 1H), 7.57 (s, 1H), 5.11(t, J = 8.5 Hz, 1H), 4.90 (dd, J = 11.4, 3.6 Hz, 1H), 3.30 (dd, J = 6.3,2.8 Hz, 1H), 3.18-3.04 (m, 1H), 2.97-2.80 (m, 2H), 2.57 (ddd, J = 13.1,11.3, 6.2 Hz, 1H), 2.26 (dd, J = 16.8, 8.4 Hz, 1H), 2.15 (dd, J = 16.9,7.7 Hz, 1H), 1.78- 1.65 (m, 2H), 1.15 (td, J = 5.0, 2.5 Hz, 1H), 0.76(dt, J = 8.7, 5.3 Hz, 1H) AE 833

LCMS-ESI (POS.) m/z 577.2 (M + H)⁺ 1H NMR (500 MHz, DMSO-d6) δ ppm 8.33-8.66 (m, 1 H), 7.42-8.22 (m, 6 H), 4.09-4.98 (m, 2 H), 3.18-3.79 (m, 4H), 2.52-2.76 (m, 1 H), 1.51- 1.90 (m, 2 H), 0.81-1.27 (m, 2H),-0.22-0.80 (m, 5 H). C (1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethoxy)phenyl)methyl)-2-(3- (methylsulfonyl)benzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide

Formulations:

A compound as disclosed herein and water were admixed together. Either30% wt/vol or 40% wt/vol of hydroxypropyl beta-cyclodextrin (HPBCD) wasadded and the mixture stirred until dissolved.

In Vitro Model of Dose-Dependent Myofibril ATPase Modulation:

Dose responses were measured using a calcium-buffered, pyruvate kinaseand lactate dehydrogenase-coupled ATPase assay containing the followingreagents (concentrations expressed are final assay concentrations):Potassium PIPES (12 mM), MgC₂ (2 mM), ATP (1 mM), DTT (1 mM), BSA (0.1mg/ml), NADH (0.5 mM), PEP (1.5 mM), pyruvate kinase (4 U/ml), lactatedehydrogenase (8 U/ml), and antifoam (90 ppm). The pH was adjusted to6.80 at 22° C. by addition of potassium hydroxide. Calcium levels werecontrolled by a buffering system containing 0.6 mM EGTA and varyingconcentrations of calcium, to achieve a free calcium concentration of1×10⁻⁴ M to 1×10⁻⁸ M.

Bovine cardiac myofibrils were obtained by homogenizing the appropriatetissue in the presence of detergent. Such treatment removes membranesand majority of soluble cytoplasmic proteins but leaves intact cardiacsarcomeric acto-myosin apparatus. Concentrations of myofibrils wereadjusted to achieve the necessary rate of ATP hydrolysis (typically0.25-1.0 mg/ml).

Chemical entity dose responses were measured at the calciumconcentration corresponding to 25% of maximal ATPase activity (pCa₂₅),so a preliminary experiment was performed to test the response of theATPase activity to free calcium concentrations in the range of 1×10⁻⁴ Mto 1×10⁻⁸ M. Subsequently, the assay mixture was adjusted to the pCa₂₅.Assays were performed by first preparing a dilution series of testchemical entity, each with an assay mixture containing potassium Pipes,MgCl₂, BSA, DTT, pyruvate kinase, lactate dehydrogenase, myofibrils,antifoam, EGTA, CaCl₂, and water. The assay was started by adding anequal volume of solution containing potassium Pipes, MgCl₂, BSA, DTT,ATP, NADH, PEP, antifoam, and water. ATP hydrolysis was monitored byabsorbance at 340 nm. The resulting dose response curve was fit by the 4parameter equation y=Bottom+((Top-Bottom)/(1+((EC50/X){circumflex over( )}Hill))). The AC1.4 is defined as the concentration at which ATPaseactivity was 1.4-fold higher than the bottom of the dose curve. AC1.4values reported in the table below are mean values based on a minimum oftwo independent tests. For compounds for which two independent testswere performed, the individual values were within two-fold of eachother. For compounds for which more than two independent tests wereperformed, the typical error is mean +/−20-30%.

AC_(1.4) AC_(1.4) AC_(1.4) AC_(1.4) EX. # (μM) EX. # (μM) EX. # (μM) EX.# (μM)  1 0.01405 204 0.4305 407 1.427 610  3.7735  2 0.01475 205 0.4322408 1.479 611  3.788  3 0.01635 206 0.43375 409 1.484 612  3.527  40.01635 207 0.4436 410 1.4853 613  3.8643  5 0.01655 208 0.4457 4111.493 614  3.8655  6 0.0171 209 0.4473 412 1.495 615  3.8905  7 0.01905210 0.4487 413 1.511 616  3.5615  8 0.0198 211 0.4488 414 1.515 617 3.626  9 0.01995 212 0.4557 415 1.522 618  3.9205  10 0.02115 2130.46035 416 1.528 619  3.929  11 0.0215 214 0.46651 417 1.53 620  3.94 12 0.0216 215 0.46655 418 1.5305 621  3.9478  13 0.0219 216 0.47455 4191.542 622  3.9515  14 0.0227 217 0.4751 420 1.5455 623  3.975  150.02315 218 0.47985 421 1.4335 624  3.658  16 0.0238 219 0.48085 4221.5655 625  4.01  17 0.02445 220 0.48095 423 1.5735 626  4.031  180.02455 221 0.4821 424 1.5805 627  4.037  19 0.02495 222 0.4825 4251.5805 628  3.83  20 0.02545 223 0.48415 426 1.4595 629  4.051  210.0266 224 0.485 427 1.5865 630  3.9185  22 0.02715 225 0.4889 428 1.606631  4.082  23 0.0287 226 0.49143 429 1.6075 632  4.0915  24 0.02875 2270.4927 430 1.474 633  4.0935  25 0.0289 228 0.4974 431 1.6305 634 4.1045  26 0.0296 229 0.5053 432 1.6518 635  4.1355  27 0.031067 2300.5074 433 1.656 636  3.919  28 0.03125 231 0.51875 434 1.66 637  3.9795 29 0.03155 232 0.5201 435 1.681 638  4.1835  30 0.0318 233 0.5241 4361.7 639  4.1855  31 0.03275 234 0.5321 437 1.7085 640  4.2315  32 0.0335235 0.5332 438 1.712 641  4.262  33 0.03455 236 0.5579 439 1.7125 642 4.2755  34 0.0361 237 0.55925 440 1.7235 643  4.3125  35 0.0372 2380.56065 441 1.7265 644  4.3367  36 0.03765 239 0.5676 442 1.7305 645 4.351  37 0.0383 240 0.56845 443 1.7885 646  4.377  38 0.0394 2410.5692 444 1.547 647  4.4125  39 0.0394 242 0.573 445 1.823 648  4.421 40 0.0398 243 0.5746 446 1.826 649  4.4365  41 0.04135 244 0.57925 4471.831 650  4.0425  42 0.042933 245 0.582 448 1.844 651  4.4705  430.043375 246 0.582 449 1.845 652  4.5245  44 0.0434 247 0.5868 4501.8545 653  4.5245  45 0.0435 248 0.59145 451 1.8635 654  4.538  460.0456 249 0.5932 452 1.8655 655  4.5443  47 0.0527 250 0.5978 4531.5515 656  4.071  48 0.0531 251 0.60545 454 1.8665 657  4.572  490.05315 252 0.6066 455 1.877 658  4.159  50 0.0546 253 0.6092 456 1.882659  4.605  51 0.0553 254 0.6139 457 1.8865 660  4.606  52 0.05535 2550.6167 458 1.5845 661  4.1595  53 0.0574 256 0.632 459 1.8995 662 4.4365  54 0.0583 257 0.63215 460 1.915 663  4.6285  55 0.0606 2580.6326 461 1.9174 664  4.669  56 0.06215 259 0.63725 462 1.9235 665 4.554  57 0.06485 260 0.63895 463 1.9305 666  4.7065  58 0.06485 2610.64605 464 1.612 667  4.708  59 0.06495 262 0.64675 465 1.9455 668 4.71  60 0.0657 263 0.6526 466 1.961 669  4.727  61 0.0687 264 0.6615467 1.9675 670  4.735  62 0.07198 265 0.6631 468 1.9855 671  4.776  630.07385 266 0.66745 469 1.9915 672  4.8355  64 0.0744 267 0.6696 4701.9915 673  4.897  65 0.0748 268 0.6764 471 1.996 674  4.9025  66 0.0766269 0.6767 472 1.807 675  4.9395  67 0.077863 270 0.668 473 2.035 676 4.59  68 0.0784 271 0.68735 474 2.036 677  4.987  69 0.08835 272 0.6904475 1.866 678  4.993  70 0.08855 273 0.6841 476 2.071 679  5.023  710.08898 274 0.6977 477 2.0765 680  5.0333  72 0.09025 275 0.69215 4782.082 681  5.0425  73 0.09745 276 0.7014 479 1.887 682  4.606  740.09935 277 0.7027 480 2.1525 683  5.096  75 0.10055 278 0.7012 4812.157 684  5.1985  76 0.1008 279 0.70924 482 1.945 685  5.246  77 0.1016280 0.713 483 2.168 686  5.284  78 0.10235 281 0.7104 484 2.014 687 5.299  79 0.10395 282 0.7195 485 2.0445 688  5.317  80 0.10455 2830.72885 486 2.202 689  5.334  81 0.1048 284 0.73315 487 2.218 690  5.354 82 0.10845 285 0.73515 488 2.1245 691  5.3575  83 0.1146 286 0.74365489 2.2325 692  5.379  84 0.1147 287 0.7212 490 2.1625 693  5.425  850.1157 288 0.7452 491 2.181 694  5.48  86 0.1312 289 0.7506 492 2.256695  5.5132  87 0.13185 290 0.7542 493 2.271 696  5.525  88 0.13445 2910.75595 494 2.274 697  5.5445  89 0.1357 292 0.7577 495 2.278 698 5.5675  90 0.13635 293 0.76035 496 2.291 699  5.5865  91 0.1384 2940.7619 497 2.3075 700  5.588  92 0.13875 295 0.7671 498 2.335 701  5.643 93 0.1413 296 0.76785 499 2.344 702  5.6535  94 0.1425 297 0.76855 5002.346 703  5.723  95 0.14463 298 0.7905 501 2.3495 704  5.725  96 0.1452299 0.79235 502 2.3515 705  5.7373  97 0.1466 300 0.7928 503 2.3565 706 5.7465  98 0.14745 301 0.79429 504 2.3635 707  5.821  99 0.14845 3020.79435 505 2.1945 708  5.8345 100 0.15015 303 0.79565 506 2.23 709 5.865 101 0.1559 304 0.74385 507 2.38 710  5.887 102 0.1574 305 0.8013508 2.3805 711  5.9075 103 0.15845 306 0.8057 509 2.3995 712  5.9215 1040.1611 307 0.8008 510 2.2505 713  6.039 105 0.16385 308 0.8085 5112.4195 714  6.0545 106 0.164 309 0.822 512 2.252 715  6.057 107 0.1642310 0.8061 513 2.3655 716  6.168 108 0.16885 311 0.8393 514 2.433 717 6.259 109 0.1712 312 0.841 515 2.441 718  6.2625 110 0.1732 313 0.8424516 2.446 719  6.2628 111 0.1746 314 0.84602 517 2.4485 720  6.27 1120.1762 315 0.8574 518 2.457 721  6.2885 113 0.17633 316 0.8325 519 2.367722  6.3585 114 0.17705 317 0.86185 520 2.5075 723  6.4425 115 0.17745318 0.86525 521 2.551 724  6.475 116 0.17905 319 0.8692 522 2.4145 725 6.507 117 0.17905 320 0.8613 523 2.582 726  6.547 118 0.1795 321 0.8725524 2.583 727  6.61 119 0.1819 322 0.87315 525 2.4285 728  6.701 1200.1826 323 0.87065 526 2.5923 729  6.7185 121 0.1828 324 0.8782 5272.5985 730  6.7333 122 0.18585 325 0.88831 528 2.4294 731  6.763 1230.189 326 0.88855 529 2.4895 732  6.7885 124 0.19985 327 0.8893 5302.614 733  6.8025 125 0.20265 328 0.8776 531 2.553 734  6.866 126 0.2062329 0.89215 532 2.6285 735  7.0265 127 0.2088 330 0.89718 533 2.5883 736 7.041 128 0.2103 331 0.8976 534 2.611 737  7.053 129 0.21185 332 0.9097535 2.69 738  7.0545 130 0.21395 333 0.92095 536 2.696 739  7.1325 1310.21584 334 0.92945 537 2.7025 740  7.156 132 0.2176 335 0.93615 5382.6115 741  7.1615 133 0.2186 336 0.9372 539 2.753 742  7.2 134 0.21985337 0.94775 540 2.7885 743  7.2015 135 0.22148 338 0.94805 541 2.789 744 7.232 136 0.2235 339 0.9511 542 2.806 745  7.244 137 0.2267 340 0.88975543 2.813 746  7.268 138 0.2306 341 0.9606 544 2.8175 747  7.287 1390.232 342 0.9661 545 2.818 748  7.314 140 0.2351 343 0.9742 546 2.6257749  7.3175 141 0.23655 344 0.95545 547 2.836 750  7.331 142 0.2421 3450.9744 548 2.66 751  7.3925 143 0.244 346 1.0139 549 2.8405 752  7.417144 0.2462 347 1.0255 550 2.8425 753  7.42 145 0.24655 348 1.0273 5512.8435 754  7.453 146 0.2474 349 1.0296 552 2.854 755  7.5435 147 0.248350 1.0349 553 2.873 756  7.5875 148 0.25685 351 1.0354 554 2.688 757 7.6005 149 0.25885 352 0.97585 555 2.893 758  7.61 150 0.25885 3531.0398 556 2.9075 759  7.6347 151 0.2616 354 1.0425 557 2.9265 760 7.661 152 0.26235 355 1.0472 558 2.928 761  7.696 153 0.26965 3561.0535 559 2.7115 762  7.747 154 0.2715 357 1.0695 560 2.9638 763  7.879155 0.27195 358 1.0947 561 2.9935 764  7.912 156 0.27265 359 1.1055 5623.025 765  7.9325 157 0.2727 360 1.11 563 2.8195 766  7.933 158 0.27295361 1.1125 564 3.077 767  8.015 159 0.2735 362 1.0375 565 3.077 768 8.033 160 0.274 363 1.143 566 3.0845 769  8.078 161 0.2746 364 1.04 5673.1075 770  8.1255 162 0.27675 365 1.139 568 3.114 771  8.1415 1630.2773 366 1.1445 569 3.182 772  8.175 164 0.27853 367 1.1962 570 3.1825773  8.21 165 0.2792 368 1.2 571 3.1845 774  8.3045 166 0.28075 3691.1795 572 3.205 775  8.31 167 0.2813 370 1.1806 573 3.224 776  8.3695168 0.28755 371 1.216 574 3.2325 777  8.3805 169 0.28915 372 1.2085 5753.245 778  8.418 170 0.29275 373 1.2258 576 2.838 779  8.423 171 0.29345374 1.2265 577 3.2945 780  8.4235 172 0.29595 375 1.2153 578 3.3475 781 8.59 173 0.3001 376 1.2296 579 3.354 782  8.6395 174 0.3052 377 1.216580 3.3545 783  8.7825 175 0.3064 378 1.227 581 3.364 784  8.852 1760.3085 379 1.237 582 3.371 785  8.8883 177 0.3113 380 1.257 583 3.3715786  8.9175 178 0.31405 381 1.268 584 3.397 787  8.931 179 0.3231 3821.232 585 3.413 788  8.9395 180 0.3256 383 1.2725 586 3.4335 789  8.9635181 0.32785 384 1.295 587 3.4385 790  8.9725 182 0.33249 385 1.3155 5883.447 791  9.007 183 0.3361 386 1.3335 589 2.881 792  9.071 184 0.33645387 1.34 590 3.4675 793  9.129 185 0.3371 388 1.3405 591 3.476 794 9.2425 186 0.33723 389 1.2325 592 3.477 795  9.3255 187 0.34095 3901.3495 593 3.49 796  9.426 188 0.3496 391 1.3505 594 3.505 797  9.447189 0.35245 392 1.268 595 3.5165 798  9.448 190 0.35695 393 1.3425 5962.9335 799  9.4535 191 0.35925 394 1.3725 597 3.5295 800  9.537 1920.3628 395 1.361 598 3.0525 801  9.578 193 0.3676 396 1.3975 599 3.5615802  9.6005 194 0.38495 397 1.361 600 3.6113 803  9.622 195 0.3859 3981.4045 601 3.276 804  9.7525 196 0.39065 399 1.4045 602 3.4595 805 9.817 197 0.39635 400 1.4048 603 3.6775 806 10 198 0.4034 401 1.378 6043.679 807  4.609 199 0.40785 402 1.381 605 3.685 808  4.6765 200 0.40827403 1.4025 606 3.696 809  4.951 201 0.411 404 1.4525 607 3.714 810 5.084 202 0.4116 405 1.4065 608 3.7405 811  8.7795 203 0.4299 4061.4675 609 3.7443 812  1.5766 813 0.7101 814 0.4802 815 2.39995 816 2.77505 817 9.11455 818 4.15535 819 1.3468 820  0.9916 821 1.2142 8225.894 823 2.76845 824  8.87405 825 9.3793 826 2.62795 827 0.15 828 0.1639 829 1.702 830 0.6694 831 0.6115 832  0.657 833 0.7424

Echocardiography/Ultrasound Protocol:

Serial echocardiography was conducted with the aid of an imaging systemsuitable for rodent cardiac ultrasound. Male CD rats (6-10 weeks of age;6-12 animals per group) were cannulated with a jugular vein catheter toenable delivery of test article by intravenous infusion. Rats wereanesthetized with inhaled isoflurane (<1.75%) delivered in oxygen (0.8L/hr) and positioned on the imaging platform, with limbs appropriatelyaligned to enable acquisition of the electrocardiogram to enable heartrat determination. Body temperature was maintained between 36-37.5degrees Celsius and baseline heart rates were maintained minimally at350 beats per minute. An imaging probe was fixed in position to acquireshort axis (SAX), motion (M)-mode images of the left cardiac ventricleat the level of the papillary muscles. Baseline data was acquired priorto initiating test article delivery. Test article (compound as disclosedherein in a HPBCD formulation), or vehicle control, was delivered withthe aid of an infusion pump connected to the jugular vein catheter.Infusion rate of test article was increased at 15 min intervals, to amaximum of 5 mL/kg/hr. Ultrasound images were acquired at 5 minintervals. Additionally whole blood (not exceeding 10 uL) was collectedvia a tail nick at the same 5 min intervals for subsequent exposuredetermination.

Whole blood samples were analyzed by protein precipitation and liquidchromatography tandem mass spectrometry (LC-MS/MS) using multiplereaction monitoring (MRM) in positive ionization mode. The lower limitof quantitation (LLOQ) in the assay was 1 ng/mL and the upper limit ofquantitation (ULOQ) was 10,000 ng/mL. Example 163 was used as aninternal standard.

Offline data analysis of the SAX M-mode ultrasound images was conductedto derive measures of left ventricular end diastolic diameter (LVEDD),left ventricular end systolic diameter (LVESD) and subsequentcalculation of fractional shortening (% FS) using the following formula:% FS=((LVEDD−LVESD)/LVEDD)*100. Minimally efficacious exposure (MEE) wasdefined as the exposure at which a 10% increase in % FS from baselinewas observed. The MEE was derived by plotting assayed exposures against% FS and using non-linear curve fitting (log(exposure) vs. % FS;variable slope, 4 parameters). Response to vehicle at each time pointwas averaged and all test article responses were normalized to baselineand subtracted from time matched (averaged) vehicle responses.

Pressure-Volume Loop (PV Loop) Protocol (Invasive Hemodynamics):

Left ventricular catheterization with a pressure-volume transducingcatheter was applied as an alternative method to derive pharmacodynamicendpoints. A pressure volume conductance catheter was inserted via theleft carotid artery and advanced into the left ventricle. The electricalsignal emitted from the volume catheter was used to derive measures ofrelative volume at 5 min intervals. From these measures, leftventricular end diastolic volume (LVEDV) and left ventricular endsystolic volume (LVESV) were derived. Ejection fraction was then derivedusing the following formula: % EF=((LVEDV−LVESV)/LVEDV)*100. Minimallyefficacious exposure (MEE) was defined as the exposure at which a 10%increase in % EF from baseline was observed. The MEE was derived byplotting assayed exposures against % EF and using non-linear curvefitting (log(exposure) vs. % EF; variable slope, 4 parameters). Responseto vehicle at each time point was averaged and all test articleresponses were normalized to baseline and subtracted from time matched(averaged) vehicle responses. Animal preparation, vehicle/test articledelivery and blood sampling for exposure determination was as describedin Echocardiography/ultrasound protocol.

MEE* Example (unbound) Formulation Protocol 67 1.05 40% HPbCD PV Loop pH4 NaOH 91 0.04 40% HPbCD PV Loop 113 0.04 40% HPbCD PV Loop 135 0.05 40%HPbCD PV Loop 200 1.02 40% HPbCD PV Loop 214 0.12 40% HPbCDEchocardiography 218 0.06 40% HPbCD Echocardiography 261 0.16 40% HPbCDPV Loop 270 0.13 40% HPbCD PV Loop 279 0.68 40% HPbCD Echocardiography287 0.47 40% HPbCD PV Loop 301 0.19 40% HPbCD PV Loop 314 0.16 40% HPbCDEchocardiography 325 0.41 40% HPbCD PV Loop 364 0.27 40% HPbCDEchocardiography and PV Loop 402 0.18 40% HPbCD PV Loop *MEE meansminimally efficacious exposure. The MEE value has been corrected for ratplasma protein binding.

What is claimed:
 1. A compound or pharmaceutically acceptable saltthereof, according to Formula (I):

wherein Q is

or a 5-member heteroaryl having 1 or 2 ring heteroatoms independentlyselected from N, O, and S which is optionally substituted with 1 or 2groups selected from C₁-C₆alkyl and halo C₁-C₆alkyl; A is absent,oxygen, N(H), N(C₁-C₆alkyl) or CR¹¹R^(11a); X¹ is N or CR²; X², X³, X⁴and X⁵ are each independently selected from N and CR³ provided that 0,1, or 2 of X¹, X², X³, X⁴ and X⁵ are N and the remainder are CR² or CR³;R^(1a) is selected from the group consisting of hydrogen, C₁-C₆alkyl andhalogen; R¹ is selected from the group consisting of hydrogen,C₁-C₆alkyl, halo C₁-C₆alkyl, hydroxy C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₇cycloalkyl optionally substituted with 1 or 2 groupsselected from hydroxy, halogen, and C₁-C₄alkyl, hydroxy C₃-C₇cycloalkyl,C₃-C₇cycloalkylC₁-C₄alkyl, hydroxy C₃-C₇cycloalkylC₁-C₄alkyl, and 4 to 7member heterocycloalkyl having 1 or 2 ring heteroatoms independentlyselected from N, O and S, which heterocycloalkyl is optionallysubstituted with 1 or 2 groups selected from oxo, hydroxy, halogen andC₁-C₄alkyl; R² is selected from the group consisting of hydrogen,halogen, C₁-C₆alkyl, haloC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₇cycloalkyl, C₃-C₇cycloalkylC₁-C₄alkyl, C₁-C₆alkoxy, haloC₁-C₆alkoxyand SF₅; or R¹ and R², taken in combination, form a divalent groupselected from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —OCH₂—, —CH₂OCH₂—, —OCH₂CH₂,—CH₂N(H)CH₂— and —CH₂N(C₁-C₄alkyl)CH₂—, each of which is optionallysubstituted with C₁-C₄alkyl or hydroxyC₁-C₄alkyl and wherein the oxygenof —OCH₂CH₂— or —OCH₂— is attached to the CR² carbon; R³ isindependently selected from the group consisting of hydrogen, halogen,C₁-C₆alkyl, haloC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl,C₃-C₇cycloalkylC₁-C₄alkyl, C₁-C₆alkoxy, haloC₁-C₆alkoxy and SF₅; R⁸ isC₁-C₆alkyl, NR^(8d)R^(8e), C₃-C₇cycloalkyl, haloC₁-C₆alkyl or benzyl,wherein each alkyl, cycloalkyl or haloalkyl is optionally substitutedwith hydroxy, CO₂H, CO₂C₁-C₆alkyl or C(O)NH₂; or R⁸ is a group of theformula:

wherein p is 1 or 2; R^(8a) is hydrogen, C₁-C₆alkyl, benzyl, or phenyloptionally substituted with C₁-C₆alkyl or halogen; R^(8b) is hydrogen,halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, haloC₁-C₆alkyl,C₁-C₆alkoxy, C₁-C₆alkoxyC₁-C₄alkyl, C₃-C₇cycloalkyl, cyano, amino,N(H)C(O)C₁-C₆alkyl, N(H)C(O)C₃-C₇cycloalkyl, N(H)C(O)haloC₁-C₆alkyl,CO₂H, C(O)NH₂, C(O)NH(C₁-C₆alkyl), C(O)N(C₁-C₆alkyl)₂, C(O)C₁-C₆alkyl,C(O)haloC₁-C₆alkyl, SO₂C₁-C₆alkyl, phenyl optionally substituted withhalogen, C₁-C₄alkyl or haloC₁-C₄alkyl, benzyl optionally substitutedwith halogen, phenoxy optionally substituted with halogen, 4 to 7 memberheterocycloalkyl having 1 or 2 ring heteroatoms selected from N, O andS, or 5 or 6 member heteroaryl having 1 ring heteroatom selected from N,O or S and 0, 1 or 2 additional ring nitrogen atoms, which heteroaryl isoptionally substituted with 1 or 2 C₁-C₆alkyl, and wherein the alkoxy isoptionally substituted with halogen, phenyl or halogen-substitutedphenyl; R^(8c) is hydrogen, halogen, hydroxy or C₁-C₆alkyl; orCR^(8b)R^(8c), taken in combination, forms a spirocyclic 3 to 6 membercarboxycle or a 4 to 6 member heterocycle having a ring heteroatomselected from N, O and S, which spirocycle is optionally substitutedwith hydroxy, C₁-C₄alkyl, haloC₁-C₄alkyl or C₁-C₄alkoxy; R^(8d) ishydrogen, C₁-C₆alkyl, haloC₁-C₆alkyl, C₃-C₇cycloalkyl, or 4 to 7 memberheterocycloalkyl having 1 ring heteroatoms selected from N, O and S and0 or 1 additional ring nitrogen atoms, which heterocycloalkyl isoptionally substituted with 1 or 2 substituents independently selectedfrom hydroxy, halogen, oxo, C₁-C₆alkyl, and C₁-C₆alkoxy; R^(8e) ishydrogen or C₁-C₆alkyl; or NR^(8d)R^(8e), taken in combination, forms a4 to 7 member heterocycloalkyl optionally comprising an additional ringheteroatom selected from N, O and S, which heterocycloalkyl isoptionally substituted with 1 or 2 substituents independently selectedfrom hydroxy, halogen, oxo, C₁-C₆alkyl, C₁-C₆alkoxy and heteroaryl,which heteroaryl has 5 or 6 ring atoms and has one ring heteroatomselected from N, O and S and 0 or 1 additional ring nitrogen atom, orNR^(8d)R^(8e), taken in combination, forms a 5 or 6 member heteroaryloptionally comprising 1 additional ring heteroatom selected from N, Oand S; R⁹ is hydrogen or C₁-C₆alkyl; R¹⁰ and R^(10a) are eachindependently selected from the group consisting of hydrogen, halogenand C₁-C₆alkyl; or R⁹ and R¹⁰ taken in combination form a divalentbridge selected from O, CH₂, and CH₂CH₂ and R^(10a) is hydrogen; R^(11a)is hydrogen or halogen; R¹² is hydrogen or halogen; R¹¹ is selected fromthe group consisting of hydrogen, halogen, C₁-C₆alkyl, N(H)C₁-C₆alkyland N(H)C₃-C₇cycloalkyl; or R¹¹ and R¹², taken in combination, form adouble bond; R^(13a) is hydrogen or C₁-C₆alkyl; R¹³ is C₁-C₆alkyl,C₃-C₇cycloalkyl or C₃-C₇cycloalkylC₁-C₆alkyl; R¹⁴ is C₁-C₅alkyl,C₃-C₇cycloalkyl or C₃-C₇cycloalkylC₁-C₆alkyl; or R¹³ and R¹⁴, taken incombination with the interposed C and N atoms, form a saturated orpartially unsaturated 4 to 7 member heterocycle which heterocyclefurther comprises 0 or 1 additional ring heteroatoms selected from N, Oand S, which heterocycle is optionally fused to a benzo ring or to asaturated carbocycle having 3 to 7 ring atoms, or which heterocycle isoptionally taken together with a saturated carbocyle having 3 to 7 ringatoms to form a spirocyclic ring, and wherein the heterocycle isoptionally substituted with 0, 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, haloC₁-C₅alkyl, C₁-C₆alkoxy,C₃-C₇cycloalkyl, O-A C(O)pyridine substituted with C₁-C₄alkyl andhaloC₁-C₄alkyl.
 2. The compound or salt of claim 1, wherein X¹ is CR²,X² is N or CR³, X³ is CR³a, X⁴ is N or CR³ and X⁵ is CR³; R² ishydrogen, halogen, C₁-C₄alkyl, cyclopropyl, haloC₁-C₄alkyl, C₁-C₄alkoxyor haloC₁-C₄alkoxy; R³ is independently selected at each occurrence fromthe group consisting of hydrogen, halogen, C₁-C₄alkyl, cyclopropyl,haloC₁-C₄alkyl, C₁-C₄alkoxy and haloC₁-C₄alkoxy; and R^(3a) is halogen,C₁-C₆alkyl, haloC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl,C₃-C₇cycloalkylC₁-C₄alkyl, C₁-C₆alkoxy, haloC₁-C₆alkoxy or SF₅.
 3. Thecompound or salt of claim 1, wherein X¹ is CR²; R² is hydrogen, halogen,C₁-C₄alkyl or C₁-C₄alkoxy; X² is CH or N; X³ is CR^(3a); R³ is halogen,C₁-C₄alkyl, haloC₁-C₄alkyl, haloC₁-C₆alkoxy or SF₅; X⁴ is CR³ or N; R³is hydrogen or halogen; and X⁵ is CH.
 4. The compound or salt of claim1, wherein X¹ is CR²; R² is hydrogen, halogen, methyl, ethyl, methoxy orethoxy; X² and X⁵ are each CH; X³ is CR^(3a); R^(3a) is halogen, methyl,ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy,or SF₅; X⁴ is CR³; and R³ is hydrogen or halogen.
 5. The compound orsalt of claim 1, wherein R¹ is selected from the group consisting ofhydrogen, C₁-C₆alkyl, halo C₁-C₆alkyl, C₃-C₇cycloalkyl,C₃-C₇cycloalkylmethyl, and 4 to 6 member heterocycloalkyl having a ringheteroatom selected from N and O, which heterocycloalkyl is optionallysubstituted with 1 or 2 groups selected from oxo, halogen, and hydroxy,and wherein the alkyl or cycloalkyl is optionally substituted withhydroxy.
 6. The compound or salt of claim 1, wherein R¹ is C₁-C₄alkyl,trifluoromethyl, C₃-C₅cycloalkyl, C₃-C₅cycloalkylmethyl, oxetanyl,tetrahydrofuryl, or azetidinyl, wherein each alkyl, cycloalkyl, oxetanylor azetidinyl is optionally substituted with hydroxy or halogen.
 7. Thecompound or salt of claim 1, wherein R¹ is methyl, isopropyl,cyclopropyl, cyclopropylmethyl, cyclobutyl, oxetanyl, difluoromethyl,1-hydroxycyclopropyl, 3-hydroxycyclobutyl, 3-hydroxy-3-methylcyclobutyl,3-fluorooxetanyl or oxopyrrolidinyl.
 8. The compound or salt of claim 1,wherein R¹³ and R¹⁴ are each independently selected from the groupconsisting of C₁-C₄alkyl, C₃-C₅cycloalkyl and C₃-C₅cycloalkylmethyl; andR^(13a) is hydrogen.
 9. The compound or salt of claim 1, wherein R¹³ andR¹⁴ are each methyl and R^(13a) is hydrogen.
 10. The compound or salt ofclaim 1, wherein R^(13a) is hydrogen; and R¹³ and R¹⁴, taken incombination with the interposed C and N atoms, form a saturated orpartially unsaturated 4 to 6 member heterocycle, which heterocyclefurther comprises 0 or 1 additional ring heteroatoms selected from N, Oand S, wherein the heterocycle is optionally fused to a saturatedcarbocycle having 3 to 7 ring atoms, or which heterocycle is optionallytaken together with a saturated carbocyle having 3 to 7 ring atoms toform a spirocyclic ring, and wherein the heterocycle is optionallysubstituted with 0, 1, 2, or 3 substituents independently selected fromthe group consisting of halogen, hydroxy, C₁-C₆alkyl, haloC₁-C₆alkyl,C₁-C₆alkoxy and C₃-C₇cycloalkyl.
 11. The compound or salt of claim 1,wherein R^(13a) is hydrogen; and R¹³ and R¹⁴, taken in combination withthe interposed C and N atoms, form a heterocyclic ring selected from thegroup consisting of azetidine, pyrrolidine, thiazolidine, piperidine andmorpholine, wherein the heterocyclic ring is optionally fused to acyclopropyl ring and the heterocyclic ring is further optionallysubstituted with 1 or 2 substituents independently selected from thegroup consisting of halogen, hydroxy, methyl, hydroxymethyl, methoxy andcyclopropyl.
 12. The compound or salt of claim 1, wherein R^(13a) ishydrogen; and R¹³ and R¹⁴, taken in combination with the interposed Cand N atoms, form a pyrrolidine ring, wherein the pyrrolidine ring isoptionally fused to a cyclopropyl ring and the pyrrolidine ring isfurther optionally substituted with 1 or 2 substituents independentlyselected from the group consisting of halogen, hydroxy, methyl,hydroxymethyl and cyclopropyl.
 13. The compound or salt of any claim 1,wherein Q is

A is oxygen, N(H), or CHR¹¹; R⁸ is C₁-C₆alkyl, NR^(8d)R^(8e),C₃-C₇cycloalkyl, haloC₁-C₆alkyl or benzyl, and wherein each alkyl,cycloalkyl or haloalkyl is optionally substituted with hydroxy, CO₂H,CO₂C₁-C₆alkyl or C(O)NH₂; or R⁸ is a group of the formula:

R^(8b) is hydrogen, C₁-C₄alkyl, halo C₁-C₄alkyl, C₁-C₄alkoxy,C₃-C₆cycloalkyl, cyano, or amino; R^(8c) is hydrogen, hydroxy orC₁-C₆alkyl; R^(8d) is hydrogen, C₁-C₆alkyl, haloC₁-C₆alkyl, orC₃-C₇cycloalkyl; R^(8e) is hydrogen or C₁-C₆alkyl; R⁹ is hydrogen; R¹⁰is hydrogen; or R⁹ and R¹⁰, taken in combination, form a divalentmethylene bridge; and R¹¹ is hydrogen or C₁-C₆alkyl.
 14. The compound orsalt of any claim 1, according to the formula:

wherein R¹ is selected from the group consisting of hydrogen,C₁-C₆alkyl, halo C₁-C₆alkyl, C₃-C₇cycloalkyl, C₃-C₇cycloalkylmethyl, and4 to 6 member heterocycloalkyl having a ring heteroatom selected from Nand O, which heterocycloalkyl is optionally substituted with 1 or 2groups selected from oxo and hydroxy, and wherein the alkyl orcycloalkyl is optionally substituted with hydroxy; R² is hydrogen,halogen, C₁-C₄alkyl or C₁-C₄alkoxy; R^(3a) is halogen, C₁-C₄alkyl,haloC₁-C₄alkyl or SF₅; X⁴ is CR³ or N; R³ is hydrogen or halogen; Z² isCH or N; Z³ is CH or N; R⁸ is C₁-C₆alkyl, C₃-C₇cycloalkyl orhaloC₁-C₆alkyl; or R⁸ is a group of the formula:

R^(8b) is halogen, C₁-C₄alkyl, haloC₁-C₄alkyl, C₁-C₄alkoxy,C₃-C₅cycloalkyl, cyano, or amino; R^(8c) is hydrogen, halogen, hydroxyor C₁-C₆alkyl; or CR^(8b)R^(8c), taken in combination, forms aspirocyclic 3 to 4 member carboxycle or a 4 or 5 member heterocyclehaving a ring heteroatom selected from N, O and S, which spirocycle isoptionally substituted with hydroxy, C₁-C₄alkyl, haloC₁-C₄alkyl orC₁-C₄alkoxy; W is a bond, CH₂, CH₂CH₂ or CH₂O, where the oxygen isadjacent to CR^(15a)R^(15b); and R^(15a) and R^(15b) are independentlyselected from the group consisting of hydrogen, halogen, hydroxy,C₁-C₄alkyl, hydroxyC₁-C₄alkyl, C₁-C₄alkoxy and C₃-C₆cycloalkyl; orR^(15a) and R^(15b), taken in combination with the carbon to which theyare attached, form a spirocyclic cyclopropyl ring; and R¹⁶ is hydrogen;or R^(15a) and R¹⁶, taken in combination with the carbon atoms to whichthey are attached, form a fused cyclopropyl ring, and R^(15b) isselected from the group consisting of hydrogen, halogen, hydroxy,C₁-C₄alkyl, hydroxyC₁-C₄alkyl, C₁-C₄alkoxy and C₃-C₆cycloalkyl.
 15. Acompound of claim 1, or a pharmaceutically acceptable salt thereofwherein the compound is selected from the group consisting of:N-((R)-(4-chloro-2-fluorophenyl)(cyclopropyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(2-fluoro-4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((R)-cyclopropyl(4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-2-cyclopropyl-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;N-(4-chloro-2,5-difluorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4,4-difluoro-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-3,3,3-trifluoro-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;(1R,3R,5R)-2-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.01hexane-3-carboxamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-3-hydroxy-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;N-(3-chloro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N-((S)-3-azetidinyl(4-chloro-2,5-difluorophenyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N-((1R)-1-(4-chloro-2,5-difluorophenypethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N-(4-chloro-3-fluorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;(3R)-4-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenypethyl)-3-morpholinecarboxamide;(4S)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-fluoro-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-((cis-3-cyanocyclobutylslfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methyl-4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyI)-D-prolinamide;N-(2-chloro-4-(trifluoromethyl)benzyI)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;(2R)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-piperidinecarboxamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-3-methyl-1-(4-(trifluoromethyl)phenyl)butyl)-D-prolinamide;N-((1R)-1-(4-chloro-3-fluorophenypethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N-(4-chloro-2-fluorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;1-(((3S)-1-(3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-N-MR)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;1-(((3R)-1-(3-cyano-1-azetidinyl)sulfonyl)-5,5-difluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-5,5-difluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;N-((1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyI)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S,4R)-1-(3-cyano-1-azetidinyl)sulfonyl)-4-methyl-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-4-methylbenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-2-hydroxv-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;(1R,2R,5S)-3-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,4-dichlorobenzyl)-D-prolinamide;N-((1R)-1-(4-chlorophenyl)-2-methoxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N-((1S)-1-(4-chlorophenyl)-2-methoxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(2-fluoro-4-methylphenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,4-dichlorobenzyl)-D-prolinamide;1-(((1R,4R,6R)-2-(3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[2.2.1hept-6-Y1)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((S)-cyclopropyl(4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;(3R)-4-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-3-morpholinecarboxamide;1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyI)-2-morpholinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((R)-cyclopropyl(4-(pentafluoro-lambda˜6˜sulfanyl)phenyl)methyl)-D-prolinamide;N-(4-chloro-2-methylbenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;1-((1-((3-cyano-1-azetidinyl)sulfonyl)-1H-pyrazol-4-yl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;N-(3-chloro-4-methylbenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;N-((R)-(4-chlorophenyl)((2R)-tetrahydro-2-furanyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyI)-3-piperidinyl)carbonyl)-D-prolinamide &N-((R)-(4-chlorophenyl)((2S)-tetrahydro-2-furanyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyI)-3-piperidinyl)carbonyl)-D-prolinamide &N-((S)-(4-chlorophenyl)((2R)-tetrahydro-2-furanyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide &N-((S)-(4-chlorophenyl)((2S)-tetrahydro-2-furanyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyI)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;N-((1R)-1-(4-chlorophenypethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N-(4-chloro-3-methylbenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-4,4-difluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methyl-3-(trifluoromethyl)benzyl)-D-prolinamide;1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;N-((1R)-1-(4-chlorophenypethyl)-1-(((3S)-1-((3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-(1H-1,2,3-triazol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N-(3-chloro-2-methylbenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,4,5-trifluorobenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(3-fluoro-4-methylphenypethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(3-fluoro-4-methylphenypethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;N-(4-chlorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(((2R)-2-(3-fluorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(((2S)-2-(3-fluorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(1-(3-cyano-1-azetidinyl)sulfonyl)-4-fluoro-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;N-((1S)-1-(4-chlorophenyl)-2-hydroxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3R,4S)-1-(3-cyano-1-azetidinyl)sulfonyl)-4-methyl-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S,4R)-1-(3-cyano-1-azetidinyl)sulfonyl)-4-methyl-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((1R,4R,6R)-2-(3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[2.2.1hept-6-yl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;N-(4-chloro-3-fluorobenzyl)-1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-D-prolinamide;(3R)-4-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenypethyl)-3-morpholinecarboxamide;N-(4-chloro-2-methoxybenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;(1S,2R,5R)-3-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0hexane-2-carboxamide;1-(((3S)-1-(((2R)-2-(3-bromophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(((2S)-2-(3-bromophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-methylbenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-fluoro-3-piperidinyl)carbonyl)- N-(4-(trifluoromethyl)benzyI)-D-prolinamide or1-(((3R)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-fluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;N-(4-chloro-2-fluorobenzyl)-1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyI)-D-prolinamide;1-(((1R,4R,6R)-2-(3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[2.2.1hept-6-yl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((1S,4S,6S)-2-(3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[2.2.1hept-6-yl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;N-(2-chloro-4-methylbenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;1-(((3S)-1-(((3S)-3-cyano-1-pyrrolidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;1-(((3S)-1-(3-ethynyl-3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyclopropyl-3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-((3-(1H-1,2,3-triazol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3-dichlorobenzyl)-D-prolinamide;(3S)-1(3-cyano-1-azetidinyl)sulfonyl)-N-((2R)-1-(((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)amino)-1-oxo-2-propanyl)-N-methyl-3-piperidinecarboxamide;1-(((3S)-1-(3-(4-chlorobenzyl)oxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;(4R)-1-(((3S)-14(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-fluoro-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,4-difluorobenzyl)-D-prolinamide;1-(((3S)-1-(3-(1,2-oxazol-3-0-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-D-prolinamide;1-(((3S)-1-(3-(2-fluoroethoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;(4R)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-hydroxy-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-4-methoxy-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-4-methoxy-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-methylbenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(3,5-difluorophenyl)propyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(4-(difluoromethyl)phenyl)ethyl)-D-prolinamide;N-((1R)-1-(4-chloro-2-fluorophenypethyl)-1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,4-dimethylbenzyl)-D-prolinamide;1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(3,4-dichlorobenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(difluoromethyl)benzyI)-D-prolinamide;N-((R)-(4-chlorophenyl)(phenyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide &N-((S)-(4-chlorophenyl)(phenyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((2S,3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-2-methyl-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;N-(3-chloro-4-fluorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide.1-(((3S)-1-(3-(difluoromethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR,3R)-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR,3S)-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS,3R)-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS,3S)-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;N-(2-chloro-4-fluorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(4-methylphenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,5-difluorobenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-2-methylbenzyl)-D-prolinamide;N-(4-chloro-2-fluorobenzyl)-1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyI)-D-prolinamide;N-((1R)-1-(4-chlorophenypethyl)-1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(2-fluoro-4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;1-(((3S)-1-(3-(difluoromethyl)-3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-3-(trifluoromethyl)benzyI)-D-prolinamide;(2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-N-((2R)-1-(((1R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)amino)-1-oxo-2-propanyl)-N-methyl-2-morpholinecarboxamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(3,4-difluorophenyl)ethyl)-D-prolinamide;1-(((3S)-1-(((2R)-2-(2-fluorophenyI)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(((2S)-2-(2-fluorophenyI)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;N-((1S)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-(2,2-difluoroethoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;N-(3-chloro-5-fluorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;(3S)-N-((2R)-1-(((1R)-1-(4-chloro-2-fluorophenyl)ethyl)amino)-1-oxo-2-propanyl)-1-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-3-piperidinecarboxamide;1-(((3S)-1-(((3R)-3-cyano-1-pyrrolidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;N-((1R)-1-(2,4-difluorophenypethyl)-1-(((3S)-1-((3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(2,4-difluorophenypethyl)-D-prolinamide;(1R,3R,5R)-2-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-2-azabicyclo]3.1.01[hexane-3-carboxamide;1-(((3S)-1-(3-cyano-3-fluoro-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-(3-hydroxy-3-(2-propanyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N-(4-chloro-3-(trifluoromethyl)benzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((2S)-4(3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(3-fluoro-4-methylbenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-3-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,4-dimethylbenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(Pentafluorobenzyl)-D-prolinamide;1-(((3S)-1-(((2R)-2-phenyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(((2S)-2-phenyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-(difluoromethoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;(1R,3R,5R)-2-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-1)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3,5-trifluorobenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((3R)-4,6-difluoro-2,3-dihydro-1-benzofuran-3-yl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((3S)-4,6-difluoro-2,3-dihydro-1-benzofuran-3-yI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-methyl-5-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,4-difluorobenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-methyl-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-((3-(1H-pyrrol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-hydroxy-3-phenyl-1-azetidinyl)sulfonyl)-3-piperidinyl)arbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-5-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-(trifluoromethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-2-methylbenzyl)-D-prolinamide;N-(4-(trifluoromethyl)benzyl)-1-(((3S)-1-(((3S)-3-(trifluoromethyl)-1-pyrrolidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-methoxy-4-methylbenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-2-methoxy1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-2-methoxy-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,5-dichlorobenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(3,5-difluorophenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,5-difluorobenzyl)-D-prolinamide;1-(((3S)-1-(3-(3-chlorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((2-(trifluoromethyl)-5-pyrimidinyl)methyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-2-hydroxy-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;N-(3-chloro-2-fluorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((6-(trifluoromethyl)-3-pyridinyl)methyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(fluoromethyl)benzyl)-D-prolinamide;(3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-MR)-1-methyl-2-oxo-2-(((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)-3-piperidinecarboxamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methoxy-4-methylbenzyl)-D-prolinamide;N-(2-chloro-3-fluorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;(2S)-N-((2R)-1-(((1R)-1-(4-chloro-2-fluorophenyl)ethyl)amino)-1-oxo-2-propanyl)-4-((3-cyano-1-azetidinyl)sulfonyl)-N-methyl-2-morpholinecarboxamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3,4,6-tetrafluorobenzyl)-D-prolinamide;1-(((3S)-1-(3-(4-chlorophenoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-((cis-3-carbamoylcyclobutyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;(4S)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-fluoro-N-(3-(trifluoromethyl)benzyl)-D-prolinamide;1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;N-(3,5-difluorobenzyl)-1-(((3S)-1-(3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;(3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-N-methyl-N-MR)-1-methyl-2-oxo-2-(4-(trifluoromethyl)benzyl)amino)ethyl)-3-piperidinecarboxamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3-dimethylbenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(difluoromethoxy)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluorobenzyl)-D-prolinamide;N-(3-chlorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-3-methylbenzyl)-D-prolinamide;N-(2-chloro-5-fluorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N-((1R)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-2,3-dihydro-1H-inden-1-yl)-D-prolinamide.1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;N-(3-chloro-5-methylbenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-3,5-dimethylbenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-cyclopropylbenzyl)-D-prolinamide;(3R)-4-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(difluoromethyl)benzyl)-3-morpholinecarboxamide;1-(((3S)-1-(3-cyclopropyl-3-fluoro-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(4-methylphenypethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(4-methylphenypethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-4-methoxybenzyl)-D-prolinamide;N-((1S)-1-(4-chloro-3-fluorophenypethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-fluoro-3-phenyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-hydroxy-3-(trifluoromethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(3,5-difluorophenyl)propyl)-D-prolinamide;1-(((3S)-1-(3(4-fluorophenyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-pyrrolidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(((3R)-2-oxo-3-azepanyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(((3S)-2-oxo-3-azepanyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-(4-fluorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyclobutyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1(3-((trifluoroacetypamino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide.1-(((3S)-1-(3-methoxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;(4S)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-fluoro-N-((1R)-1-(3-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluorobenzyl)-D-prolinamide;1-(((3S)-1(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-5-methylbenzyl)-D-prolinamide;1-(((3S)-1-(3-(methylsulfonyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((5-(trifluoromethyl)-2-pyridinyl)methyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4R)-3,4-dihydro-2H-chromen-4-yl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4S)-3,4-dihydro-2H-chromen-4-yl)-D-prolinamide;1-(((1R,4S,5R)-2-(3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[3.1.01]hex-4-yl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((1S,4R,5S)-2-(3-cyano-1-azetidinyl)sulfonyl)-2-azabicyclo[3.1.01]hex-4-yl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(5-fluoro-2-methylbenzyl)-D-prolinamide;1-(((3S)-1-(3-ethyl-3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-D-prolinamide;N-((1R)-1-(4-chlorophenyl)ethyl)-1-(((2S)-4-((3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-D-prolinamide;1-(((3R)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-fluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide or1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-fluoro-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)methyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3-difluorobenzyl)-D-prolinamide;1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-morpholinyl)carbonyl)-N-(3,5-difluorobenzyl)-D-prolinamide; methylcis-3-(((3S)-3-(((2R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)-1-pyrrolidinyl)carbonyl)-1-piperidinyl)sulfonyl)cyclobutanecarboxylate;methyl trans-3-(((3S)-3-(((2R)-2-((4-(trifluoromethyl)benzyl)carbamoyl)-1-pyrrolidinyl)carbonyl)-1-piperidinyl)sulfonyl)cyclobutanecarboxylate;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(2,5-difluorophenyl)-2,2-difluoroethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(2,5-difluorophenyl)-2,2-difluoroethyl)-D-prolinamide;N-(3-chloro-5-(trifluoromethyl)benzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;1-(((3S)-1-(3-(trifluoromethoxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1(3-(Pentyloxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3R)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(4-cyanophenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-methyl-3-(trifluoromethyl)benzyI)-D-prolinamide;N-(5-chloro-2-fluorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-cyanobenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-methoxybenzyl)-D-prolinamide;N-((R)-3-azetidinyl(4-chloro-2,5-difluorophenyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyI)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;1-(((3S)-1-((3-(1H-imidazol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;N4(7S)-bicyclo[4.2.0octa-1,3,5-trien-7-yl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methylbenzyl)-D-prolinamide;N-(2-chlorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N-((3R)-4-chloro-2,3-dihydro-1-benzofuran-3-yl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyI)-3-piperidinyl) carbonyl)-D-prolinamide &N4(3S)-4-chloro-2,3-dihydro-1-benzofuran-3-yl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-(4-pyridinyloxy)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;(4S)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-4-hydroxy-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-((3-(1H-pyrazol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;N-(2-chloro-3-methoxybenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide.1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(3-fluoro-4-methoxyphenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(3-fluoro-4-methoxyphenypethyl)-D-prolinamide;1-(((3S)-1-((trans-3-cyanocyclobutyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((cis-4-(trifluoromethyl)cyclohexyl)methyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4-(trifluoromethyl)cyclohexyl)methyl)-D-prolinamide;N-(3-chloro-4-methoxybenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(4-fluoro-3-methylphenypethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(4-fluoro-3-methylphenypethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(4-(difluoromethoxy)phenyl)ethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(4-(difluoromethoxy)phenyl)ethyl)-D-prolinamide;N-((1R)-1-(2-fluoro-4-(trifluoromethyl)pheny)ethyl)-1-(((3S)-1-((3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-3-methylbenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-6-methylbenzyl)-D-prolinamide;N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-((3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N-4(6-chloro-3-pyridinyl)methyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-methoxy-2-methylbenzyl)-D-prolinamide;N-(5-chloro-2-methylbenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-5-fluoro-6-methoxy-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-5-fluoro-6-methoxy-2,3-dihydro-1H-inden-1-yl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,3,5,6-tetrafluorobenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(4-methoxyphenyl)propyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(4-methoxyphenyl)propyl)-D-prolinamide;1-(((3S)-1-((trans-3-carbamoylcyclobutyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-hydroxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(4-(difluoromethoxy)-3-methoxyphenyl)ethyl)-D-prolinamide;1-(((3S)-1(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(4-(difluoromethoxy)-3-methoxyphenypethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(5-fluoro-2-methoxyphenypethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(5-fluoro-2-methoxyphenypethyl)-D-prolinamide;1-(((2R)-4-(3-cyano-1-azetidinyl)sulfonyl)-1-methyl-2-piperazinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-1-methyl-2-piperazinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-5-methylbenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-methylbenzyl)-D-prolinamide;1-(((3S)-1(1,1-dioxido-3-thietanyl)sulfamoyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1(3-cyano-1-azetidinyl)sulfonyl)-3-pyrrolidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,5-dichlorobenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(1-oxa-6-azaspiro[3.3.1hept-6-ylsulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((3R)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl)-D-prolinamide& 1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((3S)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-6-(trifluoromethyl)benzyI)-D-prolinamide;N-(2-chloro-5-methylbenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;N-(4-chloro-3-fluorobenzyl)-1-(((3S)-1-(3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;1-(((3S)-1-(3-oxetanylsulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;1-(((3S)-1-(3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1S)-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;N-(2-fluoro-4-(trifluoromethyl)benzyl)-1-(((3S)-1-(3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-methoxv-3-methylbenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-5-(trifluoromethyl)benzyI)-D-prolinamide; 1-(((3S)-1-((3-(1H-1,2,4-triazol-1-yl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-fluoro-5-methoxybenzyl)-D-prolinamide;(4S)-4-fluoro-1-(((3S)-1(3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluorobenzyl)-D-prolinamide;1-(((3S)-1-(3-(3-methyl-1,2,4-oxadiazol-5-0-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-((methoxyacetyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,5-difluorobenzyl)-L-prolinamide;1-(((3S)-1-(((2R)-2-(4-chlorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(((2S)-2-(4-chlorophenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((1R)-1-(2-(difluoromethoxy)-4-fluorophenypethyl)-D-prolinamide;1-(((3S)-1-(3-(4-chlorobenzyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(5-fluoro-2-methoxybenzyl)-D-prolinamide;1-(((3S)-1-(3,3-difluoro-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;N4(7R)-bicyclo[4.2.0]octa-1,3,5-trien-7-yl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;N4(7S)-bicyclo[4.2.0]octa-1,3,5-trien-7-yl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide.1-(((3S)-1-(3-(2-pyridinyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-ethoxv-3-fluorobenzyl)-D-prolinamide;1-(((3S)-1(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,6-dimethylbenzyl)-D-prolinamide;1-(((3S)-1-(3-((cyclopropylcarbonyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4R)-2-methyl-1,2,3,4-tetrahydro-4-isoquinolinyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4S)-2-methyl-1,2,3,4-tetrahydro-4-isoquinolinyI)-D-prolinamide;1-(((3S)-1-(3-(dimethylcarbamoyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-methyl-5-(trifluoromethyl)benzyl)-D-prolinamide;N-(2-chloro-6-fluorobenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(((2R)-2-benzyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(((2S)-2-benzyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;(1R,3R,5R)-N-((R)-(4-chloro-2,5-difluorophenyl)(cyclopropyl)methyl)-2-(((2S)-4-(methylsulfonyl)-2-piperazinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(4-fluorophenypethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(4-fluorophenypethyl)-D-prolinamide;1-(((3S)-1-(3-hydroxy-3-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;N-((1R)-1-(4-chlorophenyl)-2-hydroxyethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-tert-butoxy-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-pentyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-(3R)-tetrahydro-3-furanyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-(3S)-tetrahydro-3-furanyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-2,2-dimethyl-1-(4-(trifluoromethyl)phenyl)propyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(5-methyl-2-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1(6-hydroxy-6-(trifluoromethyl)-2-azaspiro[3.3.]hept-2-yl)sulfonyl)-3-piperidinyl)carbonyI)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(dimethylsulfamoyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide; 1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(((6R)-6-hydroxy-2-azaspiro[3.4loct-2-yl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(((6S)-6-hydroxy-2-azaspiro[3.4]oct-2-yl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-((cyclobutylcarbonyl)amino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;N-benzyl-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-fluoro-3-(trifluoromethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(2,3-difluorophenypethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(2,3-difluorophenypethyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2,5-dimethylbenzyl)-D-prolinamide;1-(((3S)-1-(3R)-tetrahydro-3-furanylsulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3S)-tetrahydro-3-furanylsulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide;1-(((3S)-1-(((2R)-2-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(((2S)-2-methyl-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;N-(5-chloro-2-methoxybenzyl)-1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyI)-D-prolinamide;N-(4-(trifluoromethyl)benzyl)-1-(((3S)-1-(3-(3-(trifluoromethyl)phenyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3,3-difluoro-1-pyrrolidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(((5-methyl-1,3,4-oxadiazol-2-yl)methyl)sulfamoyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide; methyltrans-3-(((3S)-3-(((2R)-2-(4-(trifluoromethyl)benzyl)carbamoyl)-1-pyrrolidinyl)carbonyl)-1-piperidinyl)sulfonyl)cyclobutanecarboxylate;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-2,2,2-trifluoro-1-(3-fluoro-4-methoxyphenypethyl)-D-prolinamide;1-(((3S)-1-(cyclobutylsulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3-(difluoromethoxy)benzyl)-D-prolinamide;1-(((3S)-1-(3-(acetylamino)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((4R)-6-methoxy-3,4-dihydro-2H-chromen-4-yl)-D-prolinamide;1-(((3S)-1-(3-(2,2,2-trifluoroethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((3S)-1-(3-(methoxymethyl)-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(3,5-dichlorobenzyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR,2R)-2-(trifluoromethyl)cyclobutyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR,2S)-2-(trifluoromethyl)cyclobutyl)-D-prolinamide;1-(((3S)-1(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS,2R)-2-(trifluoromethyl)cyclobutyl)-D-prolinamide;1-(((3S)-1(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS,2S)-2-(trifluoromethyl)cyclobutyl)-D-prolinamide;1-(((3S)-1-(1-azaspiro[3.31]hept-1-ylsulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;(1R,3S,5R)-2-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;N-((1S)-1-(4-chlorophenyl)ethyl)-1-(((3S)-1-((3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MR)-1-(2-methoxyphenyl)propyl)-D-prolinamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-MS)-1-(2-methoxyphenyl)propyl)-D-prolinamide;1-(((3S)-1-(1-acetyl-3-azetidinyl)sulfamoyl)-3-piperidinyl)carbonyl)-N-(4-(trifluoromethyl)benzyI)-D-prolinamide;(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(5-methylthiophene-2-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(1,4-dimethyl-1H-pyrazole-5-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(5-(trifluoromethyl)isoxazole-3-carbonyl)-2-azabicyclo[3.1.01]hexane-3-carboxamide;(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3,4-dimethylisoxazole-5-carbonyl)-2-azabicyclo[3.1.01]hexane-3-carboxamide;(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3,5-dimethylisoxazole-4-carbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;(1R,3R,5R)-N-((R)-(2,5-difluoro-4-(trifluoromethyl)phenyl)(oxetan-3-yl)methyl)-2-(3-(trifluoromethyl)isoxazole-5-carbonyl)-2-azabicyclo[3.1.01]hexane-3-carboxamide;and 1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-(4-(trifluoromethyl)phenyl)ethyl)-D-prolinamide.
 16. Acompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein the compound is selected from the group consisting of:(1R,3R,5R)-2-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide;1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-D-prolinamide;1-(((2S)-4-(3-cyano-1-azetidinyl)sulfonyl)-2-piperazinyl)carbonyl)-N-(2-fluoro-4-(trifluoromethyl)benzyI)-D-prolinamide;and1-(((3S)-1-(3-cyano-1-azetidinyl)sulfonyl)-3-piperidinyl)carbonyl)-N-(3,5-difluorobenzyl)-D-prolinamide..17. The compound of claim 1 in the form of a pharmaceutically acceptablesalt.
 18. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient, carrier or adjuvant and at least one compound orsalt of claim
 1. 19. The pharmaceutical composition of claim 18, whereinthe composition is formulated in a form selected from the groupconsisting of an injectable fluid, an aerosol, a tablet, a pill, acapsule, a syrup, a cream, a gel and a transdermal patch.
 20. A packagedpharmaceutical composition, comprising a pharmaceutical composition ofclaim 18 and instructions for using the composition to treat a patientsuffering from a heart disease.
 21. The packaged pharmaceuticalcomposition of claim 20, wherein the heart disease is heart failure. 22.A method of treating heart disease in a mammal which method comprisesadministering to the mammal a therapeutically effective amount of atleast one compound of claim 1, or a pharmaceutical salt thereof or apharmaceutical composition thereof.
 23. The method of claim 22, whereinthe heart disease is heart failure.
 24. The method of claim 23, whereinthe heart failure is congestive heart failure.
 25. The method of claim23, wherein the heart failure is systolic heart failure.
 26. A methodfor modulating the cardiac sarcomere in a mammal which method comprisesadministering to the mammal an amount of at least one compound of claim1 or a pharmaceutical salt thereof or a pharmaceutical compositionthereof to modulate the cardiac sarcomere in the mammal.
 27. A methodfor potentiating cardiac myosin in a mammal which method comprisesadministering to the mammal an amount of at least one compound of claim1 or a pharmaceutical salt thereof or a pharmaceutical compositionthereof to potentiate cardiac myosin in the mammal.